rs75400929

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1505C>T(p.Pro502Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00827 in 1,613,348 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P502P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0072 ( 15 hom., cov: 32)

Exomes 𝑓: 0.0084 ( 105 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.46

Publications

8 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=0.0065681934).

BP6

Variant 17-78121043-G-A is Benign according to our data. Variant chr17-78121043-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 456008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00724 (1102/152300) while in subpopulation NFE AF = 0.00906 (616/68012). AF 95% confidence interval is 0.00847. There are 15 homozygotes in GnomAd4. There are 600 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC6	NM_001127198.5 link	c.1505C>T	p.Pro502Leu	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.1505C>T	p.Pro502Leu	missense_variant	Exon 12 of 20	2	NM_001127198.5	ENSP00000465261.1		Q7Z403-1

Frequencies

GnomAD3 genomes

AF:

0.00724

AC:

1102

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00125

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0371

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00906

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00849

AC:

2126

AN:

250436

AF XY:

0.00807

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00140

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0382

Gnomad NFE exome

AF:

0.00976

Gnomad OTH exome

AF:

0.0105

GnomAD4 exome

AF:

0.00838

AC:

12247

AN:

1461048

Hom.:

105

Cov.:

AF XY:

0.00803

AC XY:

5838

AN XY:

726844

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33478

American (AMR)

AF:

0.00141

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00217

AC:

187

AN:

86258

European-Finnish (FIN)

AF:

0.0390

AC:

2050

AN:

52610

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00853

AC:

9489

AN:

1111996

Other (OTH)

AF:

0.00672

AC:

406

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

853

1706

2559

3412

4265

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.00724

AC:

1102

AN:

152300

Hom.:

Cov.:

AF XY:

0.00806

AC XY:

600

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

41560

American (AMR)

AF:

0.000719

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0371

AC:

394

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00906

AC:

616

AN:

68012

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

113

169

226

282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00774

Hom.:

Bravo

AF:

0.00447

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.00858

AC:

1042

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00540

EpiControl

AF:

0.00640

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TMC6: BS2 -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T;T;.;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

.;.;D;D;D

MetaRNN

Benign

0.0066

T;T;T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.9

M;M;M;.;.

PhyloP100

4.5

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-9.6

.;D;D;.;.

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

.;D;D;.;.

Sift4G

Uncertain

0.0020

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.39

MVP

0.69

MPC

0.68

ClinPred

0.053

GERP RS

3.9

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.79

gMVP

0.62

Mutation Taster

=73/27

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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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