Variant rs397517836 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.1369T>C(p.Phe457Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMC1
NM_138691.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.96

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:

TMC1 (HGNC:):

TMC1 links:

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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	Protein	UniProt
TMC1	NM_138691.3 linkuse as main transcript	c.1369T>C	p.Phe457Leu	missense_variant	16/24	ENST00000297784.10	NP_619636.2	Q8TDI8
TMC1	XM_017014256.2 linkuse as main transcript	c.1372T>C	p.Phe458Leu	missense_variant	13/21		XP_016869745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC1	ENST00000297784.10 linkuse as main transcript	c.1369T>C	p.Phe457Leu	missense_variant	16/24	1	NM_138691.3	ENSP00000297784.6		Q8TDI8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251242

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000163

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

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

Aug 01, 2011

Variant classified as Uncertain Significance - Favor Benign. The Phe457Leu varia nt in TMC1 has not been reported in the literature nor previously identified by our laboratory. Computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inco nsistent predictions on the pathogenicity of this variant. In summary, the clini cal significance of this variant cannot be determined with certainty at this tim e. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

T;T;.;T;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

.;.;T;T;T

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.52

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.96

L;L;.;L;.

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.7

D;.;.;D;.

REVEL

Uncertain

0.30

Sift

Benign

1.0

T;.;.;T;.

Sift4G

Benign

0.34

T;.;.;T;.

Polyphen

0.83

P;P;.;P;.

Vest4

0.93

MutPred

0.65

Loss of MoRF binding (P = 0.4565);Loss of MoRF binding (P = 0.4565);.;Loss of MoRF binding (P = 0.4565);.;

MVP

0.52

MPC

0.24

ClinPred

0.38

GERP RS

5.9

Varity_R

0.45

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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