rs114853749

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127198.5(TMC6):c.1471C>T(p.Arg491Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,613,108 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R491H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0046 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 1 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.12

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

epidermodysplasia verruciformis, susceptibility to, 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
epidermodysplasia verruciformis
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

TMC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005252272).

BP6

Variant 17-78121077-G-A is Benign according to our data. Variant chr17-78121077-G-A is described in ClinVar as [Benign]. Clinvar id is 456007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00456 (695/152324) while in subpopulation AFR AF = 0.016 (665/41572). AF 95% confidence interval is 0.015. There are 9 homozygotes in GnomAd4. There are 332 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5 link	c.1471C>T	p.Arg491Cys	missense_variant	Exon 12 of 20	ENST00000590602.6	NP_001120670.1	Q7Z403-1A0A024R8V2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6 link	c.1471C>T	p.Arg491Cys	missense_variant	Exon 12 of 20	2	NM_001127198.5	ENSP00000465261.1		Q7Z403-1

Frequencies

GnomAD3 genomes

AF:

0.00456

AC:

694

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00119

AC:

297

AN:

249378

AF XY:

0.000901

show subpopulations

Gnomad AFR exome

AF:

0.0142

Gnomad AMR exome

AF:

0.000898

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000276

Gnomad OTH exome

AF:

0.000822

GnomAD4 exome

AF:

0.000635

AC:

928

AN:

1460784

Hom.:

Cov.:

AF XY:

0.000556

AC XY:

404

AN XY:

726700

show subpopulations

African (AFR)

AF:

0.0156

AC:

521

AN:

33474

American (AMR)

AF:

0.000917

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52450

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000260

AC:

289

AN:

1111930

Other (OTH)

AF:

0.000977

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

137

206

274

343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00456

AC:

695

AN:

152324

Hom.:

Cov.:

AF XY:

0.00446

AC XY:

332

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0160

AC:

665

AN:

41572

American (AMR)

AF:

0.000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68018

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

103

138

172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.00471

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0120

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00140

AC:

170

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Epidermodysplasia verruciformis

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TMC6-related disorder

Benign:1

Jun 20, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T;T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.92

.;.;D;D;D

MetaRNN

Benign

0.0053

T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.4

M;M;M;.;.

PhyloP100

3.1

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.7

.;D;D;.;.

REVEL

Benign

0.19

Sift

Uncertain

0.022

.;D;D;.;.

Sift4G

Uncertain

0.024

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.37

MVP

0.80

MPC

0.24

ClinPred

0.021

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.23

Mutation Taster

=84/16

polymorphism

(source)

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

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rs114853749

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over