Variant 9-72792318-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The NM_138691.3(TMC1):c.1532C>T(p.Pro511Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P511H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMC1
NM_138691.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.93

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 172) in uniprot entity TMC1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_138691.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-72792318-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165436.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

PP5

Variant 9-72792318-C-T is Pathogenic according to our data. Variant chr9-72792318-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 402278.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC1	NM_138691.3 linkuse as main transcript	c.1532C>T	p.Pro511Leu	missense_variant	17/24	ENST00000297784.10
TMC1	XM_017014256.2 linkuse as main transcript	c.1535C>T	p.Pro512Leu	missense_variant	14/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC1	ENST00000297784.10 linkuse as main transcript	c.1532C>T	p.Pro511Leu	missense_variant	17/24	1	NM_138691.3	P2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 7

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Hereditary Research Laboratory, Bethlehem University

Jun 04, 2016

FA3 moderate HL at 6y; FA4 profound at 18m -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D;.;D;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.081

MetaRNN

Uncertain

0.68

D;D;D;D;D

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.6

M;M;.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.8

D;.;.;D;.

REVEL

Uncertain

0.39

Sift

Benign

0.070

T;.;.;T;.

Sift4G

Uncertain

0.049

D;.;.;D;.

Polyphen

0.80

P;P;.;P;.

Vest4

0.60

MutPred

0.45

Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);.;Gain of helix (P = 0.0349);.;

MVP

0.82

MPC

0.37

ClinPred

0.98

GERP RS

5.8

Varity_R

0.27

gMVP

0.71

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