rs12449858

Positions:

chr17-78125237-G-A

Variant summary

Our verdict is Benign. Variant got -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

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=0.0024380684).

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. Variant chr17-78125237-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
TMC6	NM_001127198.5 linkuse as main transcript	c.457C>T	p.Leu153Phe	missense_variant	6/20	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.457C>T	p.Leu153Phe	missense_variant	6/20	2	NM_001127198.5	ENSP00000465261	P1	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

GnomAD3 exomes

AF:

0.133

AC:

26661

AN:

200254

Hom.:

3085

AF XY:

0.121

AC XY:

12996

AN XY:

107504

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 SAS exome

AF:

0.0426

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

Gnomad4 AFR exome

AF:

0.0197

Gnomad4 AMR exome

AF:

0.345

Gnomad4 ASJ exome

AF:

0.121

Gnomad4 EAS exome

AF:

0.272

Gnomad4 SAS exome

AF:

0.0457

Gnomad4 FIN exome

AF:

0.108

Gnomad4 NFE exome

AF:

0.0876

Gnomad4 OTH exome

AF:

0.0936

GnomAD4 genome

AF:

0.0931

AC:

14186

AN:

152302

Hom.:

1059

Cov.:

AF XY:

0.0967

AC XY:

7204

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0261

Gnomad4 AMR

AF:

0.219

Gnomad4 ASJ

AF:

0.118

Gnomad4 EAS

AF:

0.224

Gnomad4 SAS

AF:

0.0434

Gnomad4 FIN

AF:

0.112

Gnomad4 NFE

AF:

0.0941

Gnomad4 OTH

AF:

0.0938

Alfa

AF:

0.102

Hom.:

1159

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

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 25854761) -
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 31, 2024

- -

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

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;.;.

MutationTaster

Benign

0.17

P;P;P;P;P;P

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

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

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