Genetic Variant TMC5:p.Met376Val (chr16-19460312-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001261841.2(TMC5):c.1126A>G(p.Met376Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMC5
NM_001261841.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.65

Variant links:

Genes affected

TMC5 (HGNC:22999): (transmembrane channel like 5) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

TMC5 links:

ENSG00000260592 (HGNC:):

ENSG00000260592 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2305646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC5	NM_001261841.2 link	c.1126A>G	p.Met376Val	missense_variant	Exon 6 of 22	ENST00000542583.7	NP_001248770.1	Q6UXY8-1B7Z946

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC5	ENST00000542583.7 link	c.1126A>G	p.Met376Val	missense_variant	Exon 6 of 22	2	NM_001261841.2	ENSP00000446274.2		Q6UXY8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461344

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727048

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1126A>G (p.M376V) alteration is located in exon 6 (coding exon 4) of the TMC5 gene. This alteration results from a A to G substitution at nucleotide position 1126, causing the methionine (M) at amino acid position 376 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

0.0060

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.019

.;.;T;T;.;.;T

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

T;T;T;.;T;T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.23

T;T;T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.2

.;M;M;M;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

N;N;N;N;N;N;N

REVEL

Benign

0.098

Sift

Benign

0.076

T;D;D;D;T;T;T

Sift4G

Uncertain

0.055

T;T;T;T;T;T;T

Polyphen

0.67

P;P;B;B;P;.;.

Vest4

0.51

MutPred

0.47

Gain of methylation at K379 (P = 0.1909);Gain of methylation at K379 (P = 0.1909);Gain of methylation at K379 (P = 0.1909);Gain of methylation at K379 (P = 0.1909);.;.;.;

MVP

0.30

MPC

0.25

ClinPred

0.77

GERP RS

5.3

Varity_R

0.26

gMVP

0.54

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over