9-72740177-C-T

Position:

chr9-72740177-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_138691.3(TMC1):c.421C>T(p.Arg141Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00957 in 1,613,376 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0068 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0099 ( 93 hom. )

Consequence

TMC1
NM_138691.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.615

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006860882).

BP6

Variant 9-72740177-C-T is Benign according to our data. Variant chr9-72740177-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 47873.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00676 (1028/152066) while in subpopulation NFE AF= 0.0108 (735/67946). AF 95% confidence interval is 0.0102. There are 3 homozygotes in gnomad4. There are 462 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC1	NM_138691.3 linkuse as main transcript	c.421C>T	p.Arg141Trp	missense_variant	9/24	ENST00000297784.10	NP_619636.2
TMC1	XM_017014256.2 linkuse as main transcript	c.424C>T	p.Arg142Trp	missense_variant	6/21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10 linkuse as main transcript	c.421C>T	p.Arg141Trp	missense_variant	9/24	1	NM_138691.3	ENSP00000297784	P2

Frequencies

GnomAD3 genomes

AF:

0.00677

AC:

1028

AN:

151948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00655

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00199

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0108

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00701

AC:

1763

AN:

251416

Hom.:

AF XY:

0.00709

AC XY:

963

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00468

Gnomad ASJ exome

AF:

0.0166

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00461

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00987

AC:

14417

AN:

1461310

Hom.:

Cov.:

AF XY:

0.00975

AC XY:

7086

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.00135

Gnomad4 AMR exome

AF:

0.00447

Gnomad4 ASJ exome

AF:

0.0157

Gnomad4 EAS exome

AF:

0.000278

Gnomad4 SAS exome

AF:

0.00528

Gnomad4 FIN exome

AF:

0.00281

Gnomad4 NFE exome

AF:

0.0114

Gnomad4 OTH exome

AF:

0.00827

GnomAD4 genome

AF:

0.00676

AC:

1028

AN:

152066

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

462

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00186

Gnomad4 AMR

AF:

0.00655

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.00199

Gnomad4 NFE

AF:

0.0108

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00949

Hom.:

Bravo

AF:

0.00637

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00953

AC:

ExAC

AF:

0.00698

AC:

848

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.00871

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TMC1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	This variant is associated with the following publications: (PMID: 27838790) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2011	Arg141Trp in exon 9 of TMC1: This variant is not expected to have clincial signi ficance because it has been reported in dbSNP (rs11143384) at a frequency of 0.5 % (30/5670) of control chromosomes. In addition, this residue is not well conser ved across mammals and distant species. -

Autosomal recessive nonsyndromic hearing loss 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autosomal dominant nonsyndromic hearing loss 36

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T;.;T

Eigen

Benign

-0.018

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.070

LIST_S2

Pathogenic

0.98

.;.;D;D

MetaRNN

Benign

0.0069

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.2

M;M;.;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.5

D;.;.;D

REVEL

Benign

0.14

Sift

Uncertain

0.010

D;.;.;D

Sift4G

Pathogenic

0.0010

D;.;.;D

Polyphen

0.99

D;D;.;D

Vest4

0.41

MVP

0.64

MPC

0.56

ClinPred

0.022

GERP RS

3.7

Varity_R

0.13

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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