rs139654750

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.610C>T(p.Arg204Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,597,824 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 12 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 17 hom. )

Consequence

TMC6
NM_001127198.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.687

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=0.007833868).

BP6

Variant 17-78124912-G-A is Benign according to our data. Variant chr17-78124912-G-A is described in ClinVar as [Benign]. Clinvar id is 526267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78124912-G-A is described in Lovd as [Likely_benign]. Variant chr17-78124912-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00846 (1289/152340) while in subpopulation AFR AF= 0.0283 (1176/41580). AF 95% confidence interval is 0.0269. There are 12 homozygotes in gnomad4. There are 591 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC6	NM_001127198.5 linkuse as main transcript	c.610C>T	p.Arg204Trp	missense_variant	7/20	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.610C>T	p.Arg204Trp	missense_variant	7/20	2	NM_001127198.5	ENSP00000465261	P1	Q7Z403-1

Frequencies

GnomAD3 genomes

AF:

0.00846

AC:

1288

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0283

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00307

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.00253

AC:

541

AN:

213698

Hom.:

AF XY:

0.00220

AC XY:

260

AN XY:

118044

show subpopulations

Gnomad AFR exome

AF:

0.0310

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.000108

Gnomad EAS exome

AF:

0.000420

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.0000634

Gnomad NFE exome

AF:

0.000642

Gnomad OTH exome

AF:

0.000931

GnomAD4 exome

AF:

0.00146

AC:

2108

AN:

1445484

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

990

AN XY:

718436

show subpopulations

Gnomad4 AFR exome

AF:

0.0298

Gnomad4 AMR exome

AF:

0.00170

Gnomad4 ASJ exome

AF:

0.0000775

Gnomad4 EAS exome

AF:

0.000153

Gnomad4 SAS exome

AF:

0.00112

Gnomad4 FIN exome

AF:

0.0000209

Gnomad4 NFE exome

AF:

0.000709

Gnomad4 OTH exome

AF:

0.00244

GnomAD4 genome

AF:

0.00846

AC:

1289

AN:

152340

Hom.:

Cov.:

AF XY:

0.00793

AC XY:

591

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0283

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.000717

Hom.:

Bravo

AF:

0.00966

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0186

AC:

ESP6500EA

AF:

0.000819

AC:

ExAC

AF:

0.00255

AC:

307

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Epidermodysplasia verruciformis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.13

T;T;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.089

LIST_S2

Benign

0.72

.;.;T;T;T

MetaRNN

Benign

0.0078

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.85

L;L;L;L;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.3

.;N;N;N;.

REVEL

Benign

0.045

Sift

Benign

0.041

.;D;D;T;.

Sift4G

Benign

0.29

T;T;T;T;.

Polyphen

0.0060

B;B;B;B;.

Vest4

0.22

MVP

0.26

MPC

0.17

ClinPred

0.0037

GERP RS

-0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.058

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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