rs2748427

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127198.5(TMC6):c.373T>C(p.Trp125Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,562,906 control chromosomes in the GnomAD database, including 45,052 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 7352 hom., cov: 33)

Exomes 𝑓: 0.23 ( 37700 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.17

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014621019).

BP6

Variant 17-78125783-A-G is Benign according to our data. Variant chr17-78125783-A-G is described in ClinVar as [Benign]. Clinvar id is 403546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78125783-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC6	NM_001127198.5 linkuse as main transcript	c.373T>C	p.Trp125Arg	missense_variant	5/20	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.373T>C	p.Trp125Arg	missense_variant	5/20	2	NM_001127198.5	ENSP00000465261.1		Q7Z403-1

Frequencies

GnomAD3 genomes

AF:

0.288

AC:

43730

AN:

151992

Hom.:

7334

Cov.:

show subpopulations

Gnomad AFR

AF:

0.469

Gnomad AMI

AF:

0.128

Gnomad AMR

AF:

0.220

Gnomad ASJ

AF:

0.257

Gnomad EAS

AF:

0.271

Gnomad SAS

AF:

0.306

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.209

Gnomad OTH

AF:

0.267

GnomAD3 exomes

AF:

0.238

AC:

40918

AN:

171670

Hom.:

5276

AF XY:

0.238

AC XY:

21840

AN XY:

91576

show subpopulations

Gnomad AFR exome

AF:

0.456

Gnomad AMR exome

AF:

0.191

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.283

Gnomad SAS exome

AF:

0.293

Gnomad FIN exome

AF:

0.213

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.226

GnomAD4 exome

AF:

0.226

AC:

318865

AN:

1410794

Hom.:

37700

Cov.:

AF XY:

0.227

AC XY:

158234

AN XY:

697286

show subpopulations

Gnomad4 AFR exome

AF:

0.474

Gnomad4 AMR exome

AF:

0.189

Gnomad4 ASJ exome

AF:

0.244

Gnomad4 EAS exome

AF:

0.227

Gnomad4 SAS exome

AF:

0.289

Gnomad4 FIN exome

AF:

0.207

Gnomad4 NFE exome

AF:

0.215

Gnomad4 OTH exome

AF:

0.245

GnomAD4 genome

AF:

0.288

AC:

43794

AN:

152112

Hom.:

7352

Cov.:

AF XY:

0.287

AC XY:

21360

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.469

Gnomad4 AMR

AF:

0.221

Gnomad4 ASJ

AF:

0.257

Gnomad4 EAS

AF:

0.271

Gnomad4 SAS

AF:

0.306

Gnomad4 FIN

AF:

0.209

Gnomad4 NFE

AF:

0.209

Gnomad4 OTH

AF:

0.267

Alfa

AF:

0.218

Hom.:

3492

Bravo

AF:

0.295

TwinsUK

AF:

0.217

AC:

806

ALSPAC

AF:

0.221

AC:

852

ESP6500AA

AF:

0.426

AC:

1833

ESP6500EA

AF:

0.196

AC:

1664

ExAC

AF:

0.174

AC:

19670

Asia WGS

AF:

0.301

AC:

1043

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Epidermodysplasia verruciformis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.0059

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

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.031

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

MetaRNN

Benign

0.0015

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

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-2.3

N;N;N;N;.;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Benign

4.2

.;N;N;N;.;.;.

REVEL

Benign

0.061

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

B;B;B;B;.;.;.

Vest4

0.12

MutPred

0.32

Gain of disorder (P = 6e-04);Gain of disorder (P = 6e-04);Gain of disorder (P = 6e-04);Gain of disorder (P = 6e-04);Gain of disorder (P = 6e-04);Gain of disorder (P = 6e-04);Gain of disorder (P = 6e-04);

MPC

0.28

ClinPred

0.00052

GERP RS

4.0

Varity_R

0.062

gMVP

0.51

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