rs1796993

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_138691.3(TMC1):c.241G>A(p.Glu81Lys) variant causes a missense change. The variant allele was found at a frequency of 0.192 in 1,586,800 control chromosomes in the GnomAD database, including 32,970 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 4128 hom., cov: 29)

Exomes 𝑓: 0.19 ( 28842 hom. )

Consequence

TMC1
NM_138691.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.72

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002365142).

BP6

Variant 9-72700522-G-A is Benign according to our data. Variant chr9-72700522-G-A is described in ClinVar as [Benign]. Clinvar id is 47869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-72700522-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC1	NM_138691.3 linkuse as main transcript	c.241G>A	p.Glu81Lys	missense_variant	8/24	ENST00000297784.10
TMC1	XM_017014256.2 linkuse as main transcript	c.244G>A	p.Glu82Lys	missense_variant	5/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10 linkuse as main transcript	c.241G>A	p.Glu81Lys	missense_variant	8/24	1	NM_138691.3	P2

Frequencies

GnomAD3 genomes

AF:

0.224

AC:

33917

AN:

151144

Hom.:

4116

Cov.:

show subpopulations

Gnomad AFR

AF:

0.268

Gnomad AMI

AF:

0.153

Gnomad AMR

AF:

0.267

Gnomad ASJ

AF:

0.295

Gnomad EAS

AF:

0.385

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.228

Gnomad MID

AF:

0.220

Gnomad NFE

AF:

0.166

Gnomad OTH

AF:

0.213

GnomAD3 exomes

AF:

0.241

AC:

59211

AN:

245954

Hom.:

7964

AF XY:

0.238

AC XY:

31606

AN XY:

133058

show subpopulations

Gnomad AFR exome

AF:

0.272

Gnomad AMR exome

AF:

0.343

Gnomad ASJ exome

AF:

0.277

Gnomad EAS exome

AF:

0.387

Gnomad SAS exome

AF:

0.309

Gnomad FIN exome

AF:

0.230

Gnomad NFE exome

AF:

0.164

Gnomad OTH exome

AF:

0.221

GnomAD4 exome

AF:

0.188

AC:

269945

AN:

1435538

Hom.:

28842

Cov.:

AF XY:

0.191

AC XY:

136785

AN XY:

714872

show subpopulations

Gnomad4 AFR exome

AF:

0.270

Gnomad4 AMR exome

AF:

0.329

Gnomad4 ASJ exome

AF:

0.275

Gnomad4 EAS exome

AF:

0.398

Gnomad4 SAS exome

AF:

0.311

Gnomad4 FIN exome

AF:

0.234

Gnomad4 NFE exome

AF:

0.158

Gnomad4 OTH exome

AF:

0.207

GnomAD4 genome

AF:

0.224

AC:

33952

AN:

151262

Hom.:

4128

Cov.:

AF XY:

0.230

AC XY:

16986

AN XY:

73878

show subpopulations

Gnomad4 AFR

AF:

0.268

Gnomad4 AMR

AF:

0.267

Gnomad4 ASJ

AF:

0.295

Gnomad4 EAS

AF:

0.385

Gnomad4 SAS

AF:

0.329

Gnomad4 FIN

AF:

0.228

Gnomad4 NFE

AF:

0.166

Gnomad4 OTH

AF:

0.218

Alfa

AF:

0.180

Hom.:

6595

Bravo

AF:

0.225

TwinsUK

AF:

0.160

AC:

595

ALSPAC

AF:

0.154

AC:

592

ESP6500AA

AF:

0.263

AC:

1157

ESP6500EA

AF:

0.169

AC:

1449

ExAC

AF:

0.238

AC:

28859

Asia WGS

AF:

0.343

AC:

1189

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 23, 2009	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal dominant nonsyndromic hearing loss 36

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Autosomal recessive nonsyndromic hearing loss 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T;T

Eigen

Benign

0.010

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.70

.;.;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.81

L;L;L

MutationTaster

Benign

0.00031

P;P;P

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.9

N;.;N

REVEL

Benign

0.079

Sift

Benign

0.26

T;.;T

Sift4G

Benign

0.10

T;.;T

Polyphen

0.15

B;B;B

Vest4

0.10

MPC

0.19

ClinPred

0.015

GERP RS

5.5

Varity_R

0.32

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over