VCV002563319.2 - ClinVar

NM_017849.4(TMEM127):c.541dup (p.Ala181fs)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_017849.4(TMEM127):c.541dup (p.Ala181fs)

Variation ID: 2563319 Accession: VCV002563319.2

Type and length

Duplication, 1 bp

Location

Cytogenetic: 2q11.2 2: 96253983-96253984 (GRCh38) [ NCBI UCSC ] 2: 96919721-96919722 (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 8, 2023	May 1, 2024	May 3, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_017849.4:c.541dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060319.1:p.Ala181fs	frameshift
NM_001193304.3:c.541dup	NP_001180233.1:p.Ala181fs	frameshift
NM_001407282.1:c.289dup	NP_001394211.1:p.Ala97fs	frameshift
NM_001407283.1:c.289dup	NP_001394212.1:p.Ala97fs	frameshift
NM_017849.3:c.541dupG		frameshift
NC_000002.12:g.96253985dup
NC_000002.11:g.96919723dup
NG_027695.1:g.17030dup
LRG_528:g.17030dup
LRG_528t1:c.540dup	LRG_528p1:p.Ala181Glyfs

... more HGVS ... less HGVS

Protein change

A181fs, A97fs

Other names

Canonical SPDI

NC_000002.12:96253983:CC:CCC

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

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.
TMEM127		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	775	1021

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.
Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	May 3, 2023	RCV003301480.2

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 (May 03, 2023)	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: SCV003996722.2 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Comment: The c.541dupG variant, located in coding exon 3 of the TMEM127 gene, results from a duplication of G at nucleotide position 541, causing a translational … (more) The c.541dupG variant, located in coding exon 3 of the TMEM127 gene, results from a duplication of G at nucleotide position 541, causing a translational frameshift with a predicted alternate stop codon (p.A181Gfs*45). This alteration occurs at the 3' terminus of theTMEM127 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 58 amino acids (24%) of the protein. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)

Comment:

The c.541dupG variant, located in coding exon 3 of the TMEM127 gene, results from a duplication of G at nucleotide position 541, causing a translational frameshift with a predicted alternate stop codon (p.A181Gfs*45). This alteration occurs at the 3' terminus of theTMEM127 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 58 amino acids (24%) of the protein. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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 this variant ...

Record last updated May 01, 2024

ClinVar Genomic variation as it relates to human health

NM_017849.4(TMEM127):c.541dup (p.Ala181fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...