chr17-78125237-G-A

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.457C>T(p.Leu153Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0969 in 1,583,914 control chromosomes in the GnomAD database, including 10,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 1059 hom., cov: 34)

Exomes 𝑓: 0.097 ( 9423 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.37

Publications

35 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:

ENSG00000309534 (HGNC:):

ENSG00000309534 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=0.0024380684).

BP6

Variant 17-78125237-G-A is Benign according to our data. Variant chr17-78125237-G-A is described in ClinVar as [Benign]. Clinvar id is 403545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5 link	c.457C>T	p.Leu153Phe	missense_variant	Exon 6 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.457C>T	p.Leu153Phe	missense_variant	Exon 6 of 20	2	NM_001127198.5	ENSP00000465261.1		Q7Z403-1

Frequencies

GnomAD3 genomes

AF:

0.0932

AC:

14183

AN:

152184

Hom.:

1057

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0261

Gnomad AMI

AF:

0.198

Gnomad AMR

AF:

0.218

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.224

Gnomad SAS

AF:

0.0432

Gnomad FIN

AF:

0.112

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0941

Gnomad OTH

AF:

0.0933

GnomAD2 exomes

AF:

0.133

AC:

26661

AN:

200254

AF XY:

0.121

show subpopulations

Gnomad AFR exome

AF:

0.0219

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.118

Gnomad EAS exome

AF:

0.212

Gnomad FIN exome

AF:

0.110

Gnomad NFE exome

AF:

0.0918

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.0973

AC:

139322

AN:

1431612

Hom.:

9423

Cov.:

AF XY:

0.0954

AC XY:

67702

AN XY:

709422

show subpopulations

African (AFR)

AF:

0.0197

AC:

650

AN:

33074

American (AMR)

AF:

0.345

AC:

13842

AN:

40090

Ashkenazi Jewish (ASJ)

AF:

0.121

AC:

3086

AN:

25540

East Asian (EAS)

AF:

0.272

AC:

10448

AN:

38448

South Asian (SAS)

AF:

0.0457

AC:

3758

AN:

82186

European-Finnish (FIN)

AF:

0.108

AC:

5474

AN:

50762

Middle Eastern (MID)

AF:

0.0736

AC:

422

AN:

5734

European-Non Finnish (NFE)

AF:

0.0876

AC:

96091

AN:

1096502

Other (OTH)

AF:

0.0936

AC:

5551

AN:

59276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

7441

14883

22324

29766

37207

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0931

AC:

14186

AN:

152302

Hom.:

1059

Cov.:

AF XY:

0.0967

AC XY:

7204

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0261

AC:

1084

AN:

41590

American (AMR)

AF:

0.219

AC:

3343

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

408

AN:

3468

East Asian (EAS)

AF:

0.224

AC:

1160

AN:

5168

South Asian (SAS)

AF:

0.0434

AC:

210

AN:

4834

European-Finnish (FIN)

AF:

0.112

AC:

1185

AN:

10622

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0941

AC:

6397

AN:

68006

Other (OTH)

AF:

0.0938

AC:

198

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

636

1271

1907

2542

3178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.101

Hom.:

1519

Bravo

AF:

0.104

TwinsUK

AF:

0.0852

AC:

316

ALSPAC

AF:

0.0825

AC:

318

ESP6500AA

AF:

0.0257

AC:

113

ESP6500EA

AF:

0.0939

AC:

806

ExAC

AF:

0.102

AC:

12256

Asia WGS

AF:

0.124

AC:

431

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 55% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -

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

This variant is associated with the following publications: (PMID: 25854761) -

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

Uncertain

0.36

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;T;T;.;.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.85

.;.;D;D;T;D

MetaRNN

Benign

0.0016

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.2

M;M;M;M;.;.

PhyloP100

6.4

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.0

.;D;D;D;.;.

REVEL

Benign

0.21

Sift

Uncertain

0.0050

.;D;D;D;.;.

Sift4G

Uncertain

0.013

D;D;D;D;.;.

Polyphen

0.98

D;D;D;D;.;.

Vest4

0.12

MPC

0.66

ClinPred

0.026

GERP RS

3.4

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.36

gMVP

0.53

Mutation Taster

=283/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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chr17-78125237-G-A

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