VCV002506513.1 - ClinVar

NM_018648.4(NOP10):c.47C>T (p.Thr16Met)

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.

(1)

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.

Pathogenic

no assertion criteria provided

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_018648.4(NOP10):c.47C>T (p.Thr16Met)

Variation ID: 2506513 Accession: VCV002506513.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q14 15: 34343027 (GRCh38) [ NCBI UCSC ] 15: 34635228 (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	Jul 1, 2023	Jul 1, 2023	Jun 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_018648.4:c.47C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_061118.1:p.Thr16Met	missense
NC_000015.10:g.34343027G>A
NC_000015.9:g.34635228G>A
NG_007951.1:g.38C>T
NG_011562.1:g.5135C>T
NG_191170.1:g.249G>A
NG_191171.1:g.59G>A
LRG_270:g.38C>T
LRG_345:g.5135C>T
LRG_345t1:c.47C>T	LRG_345p1:p.Thr16Met

... more HGVS ... less HGVS

Protein change

Other names

T16M

Canonical SPDI

NC_000015.10:34343026:G:A

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

OMIM: 606471.0003 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.
NOP10		-	-	GRCh38 GRCh38 GRCh37	69	113

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.
Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 2	Pathogenic (1)	no assertion criteria provided	Jun 23, 2023	RCV003236697.1

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.
Pathogenic (Jun 23, 2023)	no assertion criteria provided Method: literature only	CATARACTS, HEARING IMPAIRMENT, NEPHROTIC SYNDROME, AND ENTEROCOLITIS 2 (1 family) Affected status: not provided Allele origin: germline	OMIM Accession: SCV003935174.1 First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023	Publications: PubMed (1) PubMed: 32554502 Comment on evidence: In 2 girls from a highly consanguineous family (family B) with cataracts, hearing impairment, nephrotic syndrome, and enterocolitis-2 (CHINE2; 620425), Balogh et al. (2020) identified … (more) In 2 girls from a highly consanguineous family (family B) with cataracts, hearing impairment, nephrotic syndrome, and enterocolitis-2 (CHINE2; 620425), Balogh et al. (2020) identified a homozygous c.47C-T transition in the NOP10 gene, resulting in a thr16-to-met (T16M) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was not present in the general population. The mother of one of the affected girls had hearing impairment, but her genotype was not noted. Patient cells showed a reduced level of the mutant NOP10 protein, suggesting a possible effect on protein stability. The mutation occurred in the DKC1 (300126)-NOP10 interface in a region distinct from those implicated in dyskeratosis congenita. Although the binding interaction with DKC1 was maintained, molecular modeling and in vitro studies showed that the T16M mutation altered the hydrogen binding between NOP10 and DKC1, disrupted the catalytic pseudouridylation site, and altered the pseudouridylation capacity of the snoRNP complex. Peripheral blood cells from 1 of the patients showed a pseudouridylation defect of 18S rRNA. Despite the finding of shortened telomeres in the affected females, the authors concluded that a pseudouridylation defect causing ribosomal dysfunction is the primary driver of this unique phenotype. (less)

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Pseudouridylation defect due to DKC1 and NOP10 mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis.	Balogh E	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 32554502

Text-mined citations for this variant ...

Record last updated Feb 14, 2024

ClinVar Genomic variation as it relates to human health

NM_018648.4(NOP10):c.47C>T (p.Thr16Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...