Variant chr9-72740159-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138691.3(TMC1):c.403G>A(p.Gly135Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G135G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

TMC1
NM_138691.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.64

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC1	NM_138691.3 linkuse as main transcript	c.403G>A	p.Gly135Arg	missense_variant	9/24	ENST00000297784.10
TMC1	XM_017014256.2 linkuse as main transcript	c.406G>A	p.Gly136Arg	missense_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10 linkuse as main transcript	c.403G>A	p.Gly135Arg	missense_variant	9/24	1	NM_138691.3	P2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251388

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 01, 2011

Variant classified as Uncertain Significance - Favor Benign. The Gly135Arg varia nt in TMC1 has not been reported in the literature nor previously identified by our laboratory. This residue is conserved across mammals and birds and computati onal analyses (PolyPhen2, SIFT) suggest that the Gly135Arg variant may impact th e protein. However, this information is not predictive enough to assume pathogen icity. In summary, the clinical significance of this variant cannot be determine d with certainty at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.0030

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

D;D;.;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

.;.;D;D

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.54

D;D;D;D

MetaSVM

Benign

-0.73

MutationAssessor

Pathogenic

3.1

M;M;.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.9

D;.;.;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0060

D;.;.;D

Sift4G

Uncertain

0.015

D;.;.;D

Polyphen

1.0

D;D;.;D

Vest4

0.51

MutPred

0.31

Gain of MoRF binding (P = 0.0199);Gain of MoRF binding (P = 0.0199);.;Gain of MoRF binding (P = 0.0199);

MVP

0.76

MPC

0.76

ClinPred

0.99

GERP RS

5.6

Varity_R

0.56

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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