chr9-72694692-A-AGGAGG

Variant names:

• chr9-72694692-A-AGGAGG
• rs730880359
• NM_138691.3:c.215_219dupGGAGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_138691.3(TMC1):​c.215_219dupGGAGG​(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
• Publications: 1 publications found

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]

TMC1 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 7

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen
• autosomal dominant nonsyndromic hearing loss 36

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 CliVar as Pathogenic. Clinvar id is 179431.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-72694692-A-AGGAGG is described in CliVar as Pathogenic. Clinvar id is 179431.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-72694692-A-AGGAGG is described in CliVar as Pathogenic. Clinvar id is 179431.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-72694692-A-AGGAGG is described in CliVar as Pathogenic. Clinvar id is 179431.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-72694692-A-AGGAGG is described in CliVar 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 rank	MANE	Protein	UniProt
TMC1	NM_138691.3	c.215_219dupGGAGG	p.Arg74GlyfsTer4	frameshift_variant	Exon 7 of 24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2	c.218_222dupGGAGG	p.Arg75GlyfsTer4	frameshift_variant	Exon 4 of 21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10	c.215_219dupGGAGG	p.Arg74GlyfsTer4	frameshift_variant	Exon 7 of 24	1	NM_138691.3	ENSP00000297784.6

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

Nov 26, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs730880359; hg19: chr9-75309608;