rs730880359

Positions:

• chr9-72694692-A-AGGAGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138691.3(TMC1):​c.215_219dup​(p.Arg74GlyfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMC1 NM_138691.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.36

Genes affected

TMC1 (HGNC:16513): (transmembrane channel like 1) This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-72694692-A-AGGAGG is Pathogenic according to our data. Variant chr9-72694692-A-AGGAGG is described in ClinVar as [Pathogenic]. Clinvar id is 179431.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC1	NM_138691.3	c.215_219dup	p.Arg74GlyfsTer4	frameshift_variant	7/24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.218_222dup	p.Arg75GlyfsTer4	frameshift_variant	4/21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.215_219dup	p.Arg74GlyfsTer4	frameshift_variant	7/24	1	NM_138691.3	ENSP00000297784	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 26, 2013

The Arg74fs variant in TMC1 has not been previously reported in individuals with hearing loss or in large population studies. This frameshift variant is predict ed to alter the protein?s amino acid sequence beginning at position 74 and lead to a premature termination codon 4 amino acids downstream. This alteration is th en predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LM M). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730880359; hg19: chr9-75309608;