rs34712518

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127198.5(TMC6):c.572G>A(p.Gly191Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0695 in 1,598,844 control chromosomes in the GnomAD database, including 4,431 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 860 hom., cov: 34)

Exomes 𝑓: 0.067 ( 3571 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.62

Publications

22 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=0.0011823177).

BP6

Variant 17-78124950-C-T is Benign according to our data. Variant chr17-78124950-C-T is described in ClinVar as Benign. ClinVar VariationId is 1164814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5 link	c.572G>A	p.Gly191Asp	missense_variant	Exon 7 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.572G>A	p.Gly191Asp	missense_variant	Exon 7 of 20	2	NM_001127198.5	ENSP00000465261.1		Q7Z403-1

Frequencies

GnomAD3 genomes

AF:

0.0925

AC:

14074

AN:

152196

Hom.:

857

Cov.:

show subpopulations

Gnomad AFR

AF:

0.174

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0485

Gnomad ASJ

AF:

0.0988

Gnomad EAS

AF:

0.0961

Gnomad SAS

AF:

0.0561

Gnomad FIN

AF:

0.0615

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0605

Gnomad OTH

AF:

0.0833

GnomAD2 exomes

AF:

0.0657

AC:

14267

AN:

217266

AF XY:

0.0644

show subpopulations

Gnomad AFR exome

AF:

0.178

Gnomad AMR exome

AF:

0.0304

Gnomad ASJ exome

AF:

0.0919

Gnomad EAS exome

AF:

0.0923

Gnomad FIN exome

AF:

0.0592

Gnomad NFE exome

AF:

0.0600

Gnomad OTH exome

AF:

0.0617

GnomAD4 exome

AF:

0.0671

AC:

96994

AN:

1446530

Hom.:

3571

Cov.:

AF XY:

0.0660

AC XY:

47465

AN XY:

718814

show subpopulations

African (AFR)

AF:

0.177

AC:

5906

AN:

33288

American (AMR)

AF:

0.0329

AC:

1428

AN:

43366

Ashkenazi Jewish (ASJ)

AF:

0.0942

AC:

2436

AN:

25868

East Asian (EAS)

AF:

0.0850

AC:

3339

AN:

39270

South Asian (SAS)

AF:

0.0540

AC:

4574

AN:

84724

European-Finnish (FIN)

AF:

0.0547

AC:

2610

AN:

47718

Middle Eastern (MID)

AF:

0.0401

AC:

220

AN:

5492

European-Non Finnish (NFE)

AF:

0.0652

AC:

72217

AN:

1107054

Other (OTH)

AF:

0.0714

AC:

4264

AN:

59750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

5891

11782

17672

23563

29454

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2876

5752

8628

11504

14380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0925

AC:

14082

AN:

152314

Hom.:

860

Cov.:

AF XY:

0.0924

AC XY:

6882

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.174

AC:

7219

AN:

41566

American (AMR)

AF:

0.0484

AC:

741

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0988

AC:

343

AN:

3472

East Asian (EAS)

AF:

0.0961

AC:

498

AN:

5180

South Asian (SAS)

AF:

0.0561

AC:

271

AN:

4828

European-Finnish (FIN)

AF:

0.0615

AC:

653

AN:

10622

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0606

AC:

4119

AN:

68022

Other (OTH)

AF:

0.0819

AC:

173

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

659

1317

1976

2634

3293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

154

308

462

616

770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0707

Hom.:

364

Bravo

AF:

0.0945

TwinsUK

AF:

0.0650

AC:

241

ALSPAC

AF:

0.0672

AC:

259

ESP6500AA

AF:

0.152

AC:

664

ESP6500EA

AF:

0.0613

AC:

524

ExAC

AF:

0.0623

AC:

7481

Asia WGS

AF:

0.0610

AC:

212

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epidermodysplasia verruciformis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.58

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.020

T;T;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.51

.;.;T;T;T

MetaRNN

Benign

0.0012

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;M;M;M;.

PhyloP100

-2.6

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.81

.;N;N;N;.

REVEL

Benign

0.032

Sift

Benign

0.71

.;T;T;T;.

Sift4G

Benign

0.23

T;T;T;T;.

Polyphen

0.0080

B;B;B;B;.

Vest4

0.044

MPC

0.21

ClinPred

0.0087

GERP RS

-5.2

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.072

gMVP

0.31

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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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