VCV000445774.4 - ClinVar

NM_006895.3(HNMT):c.475del (p.His159fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006895.3(HNMT):c.475del (p.His159fs)

Variation ID: 445774 Accession: VCV000445774.4

Type and length

Deletion, 1 bp

Location

Cytogenetic: 2q22.1 2: 138005176 (GRCh38) [ NCBI UCSC ] 2: 138762746 (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	Nov 5, 2017	Jan 6, 2024	Nov 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006895.3:c.475del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_008826.1:p.His159fs	frameshift
NM_006895.3:c.475delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000002.12:g.138005177del
NC_000002.11:g.138762747del
NG_012966.1:g.45940del

... more HGVS ... less HGVS

Protein change

H159fs

Other names

Canonical SPDI

NC_000002.12:138005175:CC:C

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.

Links

ClinGen: CA1891789 dbSNP: rs765863580 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.
HNMT		-	-	GRCh38 GRCh37	41	64

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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Apr 17, 2017	RCV000514118.2
Inherited susceptibility to asthma Intellectual disability, autosomal recessive 51	Likely pathogenic (1)	criteria provided, single submitter	Jun 10, 2022	RCV003227774.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Nov 15, 2023	RCV003479148.1

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.
Likely pathogenic (Apr 17, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000610474.1 First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017
Likely pathogenic (Jun 10, 2022)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Intellectual disability, autosomal recessive 51 Inherited susceptibility to asthma Affected status: unknown Allele origin: inherited	New York Genome Center Accession: SCV003925170.1 First in ClinVar: May 20, 2023 Last updated: May 20, 2023	Comment: The c.475del variant in HNMT has not previously been reported in the literature but it has been deposited in ClinVar [ClinVar ID: 445774] as Likely … (more) The c.475del variant in HNMT has not previously been reported in the literature but it has been deposited in ClinVar [ClinVar ID: 445774] as Likely pathogenic. The c.475del variant is observed in 21 alleles (~0.00004% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMedFreeze 8. All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.475del variant in HNMT is located in exon 5 of this 6-exon gene, and is predicted to incorporate a premature termination codon (p.(His159IlefsTer4), which might result in either loss-of-function via nonsense mediated decay or loss of the last 129 amino acids (>10% of the protein). Based on available evidence this inherited c.475del p.(His159IlefsTer4) variant identified in HNMT is classified as Likely Pathogenic. (less) Clinical Features: Global developmental delay (present) , Macrocephaly (present) , Attention deficit hyperactivity disorder (present) , Hypotonia (present) , Atrial septal defect (present) Secondary finding: no
Uncertain significance (Nov 15, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004222692.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: Variant summary: HNMT c.475delC (p.His159IlefsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: HNMT c.475delC (p.His159IlefsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in HNMT as causative of disease. The variant allele was found at a frequency of 6e-05 in 250516 control chromosomes (i.e., 15 heterozygotes; gnomAD v2 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.475delC in individuals affected with HNMT-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and both submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)

Comment:

The c.475del variant in HNMT has not previously been reported in the literature but it has been deposited in ClinVar [ClinVar ID: 445774] as Likely pathogenic. The c.475del variant is observed in 21 alleles (~0.00004% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMedFreeze 8. All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.475del variant in HNMT is located in exon 5 of this 6-exon gene, and is predicted to incorporate a premature termination codon (p.(His159IlefsTer4), which might result in either loss-of-function via nonsense mediated decay or loss of the last 129 amino acids (>10% of the protein). Based on available evidence this inherited c.475del p.(His159IlefsTer4) variant identified in HNMT is classified as Likely Pathogenic.

Comment:

Variant summary: HNMT c.475delC (p.His159IlefsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss-of-function variants in HNMT as causative of disease. The variant allele was found at a frequency of 6e-05 in 250516 control chromosomes (i.e., 15 heterozygotes; gnomAD v2 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.475delC in individuals affected with HNMT-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and both submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs765863580 ...

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 Jan 06, 2024

ClinVar Genomic variation as it relates to human health

NM_006895.3(HNMT):c.475del (p.His159fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs765863580 ...