Variant rs146371375 details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001127198.5(TMC6):c.838G>T(p.Ala280Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.312

Variant links:

Genes affected

TMC6 (HGNC:18021): (transmembrane channel like 6) Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human papillomaviruses (HPVs) and a high rate of progression to squamous cell carcinoma on sun-exposed skin. EV is caused by mutations in either of two adjacent genes located on chromosome 17q25.3. Both of these genes encode integral membrane proteins that localize to the endoplasmic reticulum and are predicted to form transmembrane channels. This gene encodes a transmembrane channel-like protein with 10 transmembrane domains and 2 leucine zipper motifs. [provided by RefSeq, Jul 2008]

TMC6 links:

TMC6 (HGNC:):

TMC6 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
TMC6	NM_001127198.5 linkuse as main transcript	c.838G>T	p.Ala280Ser	missense_variant	8/20	ENST00000590602.6	NP_001120670.1	Q7Z403-1A0A024R8V2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6 linkuse as main transcript	c.838G>T	p.Ala280Ser	missense_variant	8/20	2	NM_001127198.5	ENSP00000465261.1		Q7Z403-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000413

AC:

AN:

242200

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132986

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:

0.00000924

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459820

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726174

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.6

DANN

Benign

0.77

DEOGEN2

Benign

0.0052

T;T;T;.;.;.

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.46

.;.;T;T;T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.082

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L;L;L;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.080

.;N;N;N;.;.

REVEL

Benign

0.038

Sift

Benign

0.66

.;T;T;T;.;.

Sift4G

Benign

1.0

T;T;T;T;T;.

Polyphen

0.0030

B;B;B;B;B;.

Vest4

0.14

MutPred

0.36

Gain of glycosylation at A280 (P = 8e-04);Gain of glycosylation at A280 (P = 8e-04);Gain of glycosylation at A280 (P = 8e-04);Gain of glycosylation at A280 (P = 8e-04);.;Gain of glycosylation at A280 (P = 8e-04);

MVP

0.26

MPC

0.15

ClinPred

0.060

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.016

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: 16

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over