9-72788472-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_138691.3(TMC1):c.1018A>G(p.Met340Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M340T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

TMC1
NM_138691.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.19

Publications

1 publications found

Variant links:

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

TMC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 0.85843 (below the threshold of 3.09). Trascript score misZ: 1.5687 (below the threshold of 3.09). GenCC associations: The gene is linked to nonsyndromic genetic hearing loss, autosomal recessive nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 36, hearing loss, autosomal recessive, autosomal dominant nonsyndromic hearing loss.

BP4

Computational evidence support a benign effect (MetaRNN=0.18777308).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3 link	c.1018A>G	p.Met340Val	missense_variant	Exon 14 of 24	ENST00000297784.10	NP_619636.2	Q8TDI8
TMC1	XM_017014256.2 link	c.1021A>G	p.Met341Val	missense_variant	Exon 11 of 21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10 link	c.1018A>G	p.Met340Val	missense_variant	Exon 14 of 24	1	NM_138691.3	ENSP00000297784.6		Q8TDI8

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251384

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000841

AC:

123

AN:

1461702

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000103

AC:

115

AN:

1111870

Other (OTH)

AF:

0.0000331

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41448

American (AMR)

AF:

0.0000655

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Met340Val variant in TMC1 has not been previously reported in individuals with hearing loss, but has been identified in 2/11550 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computation al prediction tools and conservation analyses suggest that the p.Met340Val varia nt may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Met340 Val variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Sep 21, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1018A>G (p.M340V) alteration is located in exon 14 (coding exon 10) of the TMC1 gene. This alteration results from a A to G substitution at nucleotide position 1018, causing the methionine (M) at amino acid position 340 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Oct 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 340 of the TMC1 protein (p.Met340Val). This variant is present in population databases (rs771281791, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with TMC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 229313). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TMC1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.091

T;T;.;T;.

Eigen

Benign

-0.064

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;.;D;D;D

M_CAP

Benign

0.0084

MetaRNN

Benign

0.19

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

L;L;.;L;.

PhyloP100

9.2

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.0

N;.;.;N;.

REVEL

Benign

0.26

Sift

Benign

0.49

T;.;.;T;.

Sift4G

Uncertain

0.0030

D;.;.;D;.

Polyphen

0.0020

B;B;.;B;.

Vest4

0.42

MVP

0.57

MPC

0.17

ClinPred

0.18

GERP RS

5.8

Varity_R

0.32

gMVP

0.55

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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9-72788472-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over