VCV000577152.17 - ClinVar

NM_177438.3(DICER1):c.4449G>A (p.Met1483Ile)

Germline

Top reviewed classifications are shown here.

Submission summary:

7 submissions

7 submitters

5 conditions

Reviewed by expert panel

Uncertain significance

Jan 2024 by ClinGen DICER1… FDA Recognized Database

for DICER1-related tumor predisposition

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_177438.3(DICER1):c.4449G>A (p.Met1483Ile)

Variation ID: 577152 Accession: VCV000577152.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q32.13 14: 95096471 (GRCh38) [ NCBI UCSC ] 14: 95562808 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 10, 2018	May 1, 2024	Jan 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_177438.3:c.4449G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_803187.1:p.Met1483Ile	missense
NM_001195573.1:c.4449G>A	NP_001182502.1:p.Met1483Ile	missense
NM_001271282.3:c.4449G>A	NP_001258211.1:p.Met1483Ile	missense
NM_001291628.2:c.4449G>A	NP_001278557.1:p.Met1483Ile	missense
NM_030621.4:c.4449G>A	NP_085124.2:p.Met1483Ile	missense
NC_000014.9:g.95096471C>T
NC_000014.8:g.95562808C>T
NG_016311.1:g.65952G>A
LRG_492:g.65952G>A
LRG_492t1:c.4449G>A	LRG_492p1:p.Met1483Ile

... more HGVS ... less HGVS

Protein change

M1483I

Other names

NM_177438.3(DICER1):c.4449G>A
p.Met1483Ile

Canonical SPDI

NC_000014.9:95096470:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

dbSNP: rs1454569806 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
DICER1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	6484	6522

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
DICER1-related tumor predisposition	Uncertain significance (2)	reviewed by expert panel	Jan 9, 2024	RCV000699832.10
DICER1-related tumor predisposition Euthyroid goiter Rhabdomyosarcoma, embryonal, 2	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000765193.3
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Jul 15, 2022	RCV001022497.5
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 26, 2023	RCV003126910.4
Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome	Uncertain significance (1)	criteria provided, single submitter	Sep 8, 2023	RCV003465610.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jan 09, 2024)	reviewed by expert panel (ClinGen DICER1 ACMG Specifications DICER1 V1.2.0) Method: curation	DICER1-related tumor predisposition (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV004231833.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7c2d7e8f-25f6-4005-b0cc-81f6f123334b Comment: The NM_177438.2:c.4449G>A variant in DICER1 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 1483 (p.Met1483Ile). The highest population … (more) The NM_177438.2:c.4449G>A variant in DICER1 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 1483 (p.Met1483Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005782 (2/34590 alleles) in the Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.039; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.2.0; 01/09/2024). (less)
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Euthyroid goiter Rhabdomyosarcoma, embryonal, 2 Pleuropulmonary blastoma Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000896428.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Jan 26, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003803396.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
Uncertain significance (Sep 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004193380.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Oct 03, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003834665.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Dec 21, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	DICER1-related tumor predisposition Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000828561.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1483 of the DICER1 protein (p.Met1483Ile). … (more) This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1483 of the DICER1 protein (p.Met1483Ile). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 577152). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jul 15, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001184244.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The p.M1483I variant (also known as c.4449G>A), located in coding exon 22 of the DICER1 gene, results from a G to A substitution at nucleotide … (more) The p.M1483I variant (also known as c.4449G>A), located in coding exon 22 of the DICER1 gene, results from a G to A substitution at nucleotide position 4449. The methionine at codon 1483 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The NM_177438.2:c.4449G>A variant in DICER1 is a missense variant predicted to cause substitution of methionine by isoleucine at amino acid 1483 (p.Met1483Ile). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005782 (2/34590 alleles) in the Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.039; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BP4. (Bayesian Points: -1; VCEP specifications version 1.2.0; 01/09/2024).

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Comment:

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1483 of the DICER1 protein (p.Met1483Ile). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 577152). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.M1483I variant (also known as c.4449G>A), located in coding exon 22 of the DICER1 gene, results from a G to A substitution at nucleotide position 4449. The methionine at codon 1483 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7c2d7e8f-25f6-4005-b0cc-81f6f123334b	-	-	-	-

Text-mined citations for rs1454569806 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_177438.3(DICER1):c.4449G>A (p.Met1483Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1454569806 ...