rs373631928

Positions:

chr17-78124968-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001127198.5(TMC6):c.554C>T(p.Pro185Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000602 in 1,593,448 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: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.40

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.007686585).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000315 (48/152344) while in subpopulation AFR AF= 0.00103 (43/41578). AF 95% confidence interval is 0.000789. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC6	NM_001127198.5 linkuse as main transcript	c.554C>T	p.Pro185Leu	missense_variant	7/20	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.554C>T	p.Pro185Leu	missense_variant	7/20	2	NM_001127198.5	ENSP00000465261.1		Q7Z403-1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000865

AC:

AN:

208172

Hom.:

AF XY:

0.0000787

AC XY:

AN XY:

114322

show subpopulations

Gnomad AFR exome

AF:

0.00126

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000361

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000220

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000333

AC:

AN:

1441104

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

715732

show subpopulations

Gnomad4 AFR exome

AF:

0.000933

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000238

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000905

Gnomad4 OTH exome

AF:

0.0000839

GnomAD4 genome

AF:

0.000315

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000331

Hom.:

Bravo

AF:

0.000427

ESP6500AA

AF:

0.000461

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000125

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Epidermodysplasia verruciformis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 185 of the TMC6 protein (p.Pro185Leu). This variant is present in population databases (rs373631928, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with TMC6-related conditions. ClinVar contains an entry for this variant (Variation ID: 526240). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.18

DANN

Benign

0.86

DEOGEN2

Benign

0.010

T;T;T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.61

.;.;T;T;T

M_CAP

Benign

0.047

MetaRNN

Benign

0.0077

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.78

N;N;N;N;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.86

.;N;N;N;.

REVEL

Benign

0.0060

Sift

Benign

0.24

.;T;T;T;.

Sift4G

Benign

0.59

T;T;T;T;.

Polyphen

0.0010

B;B;B;B;.

Vest4

0.12

MVP

0.048

MPC

0.16

ClinPred

0.0097

GERP RS

-7.1

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.032

gMVP

0.13

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