chr9-72792243-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_138691.3(TMC1):c.1457T>C(p.Met486Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0226 in 1,614,168 control chromosomes in the GnomAD database, including 623 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 33 hom., cov: 32)

Exomes 𝑓: 0.023 ( 590 hom. )

Consequence

TMC1
NM_138691.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.64

Publications

16 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: Benign. The variant received -19 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=0.0026560128).

BP6

Variant 9-72792243-T-C is Benign according to our data. Variant chr9-72792243-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC1	NM_138691.3 link	c.1457T>C	p.Met486Thr	missense_variant	Exon 17 of 24	ENST00000297784.10	NP_619636.2	Q8TDI8
TMC1	XM_017014256.2 link	c.1460T>C	p.Met487Thr	missense_variant	Exon 14 of 21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10 link	c.1457T>C	p.Met486Thr	missense_variant	Exon 17 of 24	1	NM_138691.3	ENSP00000297784.6		Q8TDI8

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2694

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00379

Gnomad AMI

AF:

0.0636

Gnomad AMR

AF:

0.00942

Gnomad ASJ

AF:

0.0631

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0520

Gnomad FIN

AF:

0.0265

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0227

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0236

AC:

5945

AN:

251456

AF XY:

0.0267

show subpopulations

Gnomad AFR exome

AF:

0.00437

Gnomad AMR exome

AF:

0.00705

Gnomad ASJ exome

AF:

0.0574

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0250

Gnomad NFE exome

AF:

0.0221

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0231

AC:

33829

AN:

1461856

Hom.:

590

Cov.:

AF XY:

0.0247

AC XY:

17978

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00323

AC:

108

AN:

33480

American (AMR)

AF:

0.00803

AC:

359

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0561

AC:

1466

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39694

South Asian (SAS)

AF:

0.0620

AC:

5346

AN:

86258

European-Finnish (FIN)

AF:

0.0240

AC:

1281

AN:

53420

Middle Eastern (MID)

AF:

0.0333

AC:

192

AN:

5768

European-Non Finnish (NFE)

AF:

0.0212

AC:

23593

AN:

1111984

Other (OTH)

AF:

0.0245

AC:

1479

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

2114

4228

6341

8455

10569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

930

1860

2790

3720

4650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0177

AC:

2696

AN:

152312

Hom.:

Cov.:

AF XY:

0.0176

AC XY:

1314

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00378

AC:

157

AN:

41574

American (AMR)

AF:

0.00941

AC:

144

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0631

AC:

219

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.0524

AC:

253

AN:

4826

European-Finnish (FIN)

AF:

0.0265

AC:

281

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0227

AC:

1541

AN:

68016

Other (OTH)

AF:

0.0170

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

142

284

426

568

710

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0210

Hom.:

159

Bravo

AF:

0.0150

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0259

AC:

223

ExAC

AF:

0.0249

AC:

3023

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.0233

EpiControl

AF:

0.0244

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 13, 2009

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 20, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:3

Dec 10, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 36

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal recessive nonsyndromic hearing loss 7

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.11

T;T;.;T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

0.085

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

.;.;T;T;T

MetaRNN

Benign

0.0027

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.44

N;N;.;N;.

PhyloP100

4.6

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.1

N;.;.;N;.

REVEL

Benign

0.047

Sift

Benign

0.25

T;.;.;T;.

Sift4G

Uncertain

0.027

D;.;.;D;.

Polyphen

0.0030

B;B;.;B;.

Vest4

0.13

MPC

0.19

ClinPred

0.0070

GERP RS

6.0

Varity_R

0.22

gMVP

0.80

Mutation Taster

=99/1

polymorphism (auto)

(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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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