rs75400929

Positions:

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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:

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=0.0065681934).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC6	NM_001127198.5 linkuse as main transcript	c.1505C>T	p.Pro502Leu	missense_variant	12/20	ENST00000590602.6	NP_001120670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC6	ENST00000590602.6 linkuse as main transcript	c.1505C>T	p.Pro502Leu	missense_variant	12/20	2	NM_001127198.5	ENSP00000465261	P1	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

GnomAD3 exomes

AF:

0.00849

AC:

2126

AN:

250436

Hom.:

AF XY:

0.00807

AC XY:

1095

AN XY:

135688

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 SAS exome

AF:

0.00203

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

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.00103

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00217

Gnomad4 FIN exome

AF:

0.0390

Gnomad4 NFE exome

AF:

0.00853

Gnomad4 OTH exome

AF:

0.00672

GnomAD4 genome

AF:

0.00724

AC:

1102

AN:

152300

Hom.:

Cov.:

AF XY:

0.00806

AC XY:

600

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00125

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0371

Gnomad4 NFE

AF:

0.00906

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00764

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	TMC6: BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Epidermodysplasia verruciformis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

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

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;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

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

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