17-78134494-A-T

Position:

chr17-78134494-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152468.5(TMC8):c.917A>T(p.Asn306Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,613,692 control chromosomes in the GnomAD database, including 202,590 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. N306N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.55 ( 23584 hom., cov: 32)

Exomes 𝑓: 0.49 ( 179006 hom. )

Consequence

TMC8
NM_152468.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.971

Variant links:

Genes affected

TMC8 (HGNC:20474): (transmembrane channel like 8) 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 8 predicted transmembrane domains and 3 leucine zipper motifs. [provided by RefSeq, Jul 2008]

TMC8 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=9.422793E-6).

BP6

Variant 17-78134494-A-T is Benign according to our data. Variant chr17-78134494-A-T is described in ClinVar as [Benign]. Clinvar id is 403548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78134494-A-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC8	NM_152468.5 linkuse as main transcript	c.917A>T	p.Asn306Ile	missense_variant	8/16	ENST00000318430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC8	ENST00000318430.10 linkuse as main transcript	c.917A>T	p.Asn306Ile	missense_variant	8/16	1	NM_152468.5	P2	Q8IU68-1

Frequencies

GnomAD3 genomes

AF:

0.549

AC:

83414

AN:

151862

Hom.:

23541

Cov.:

show subpopulations

Gnomad AFR

AF:

0.677

Gnomad AMI

AF:

0.409

Gnomad AMR

AF:

0.576

Gnomad ASJ

AF:

0.539

Gnomad EAS

AF:

0.432

Gnomad SAS

AF:

0.507

Gnomad FIN

AF:

0.484

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.490

Gnomad OTH

AF:

0.537

GnomAD3 exomes

AF:

0.512

AC:

128377

AN:

250684

Hom.:

33564

AF XY:

0.508

AC XY:

68884

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.683

Gnomad AMR exome

AF:

0.562

Gnomad ASJ exome

AF:

0.537

Gnomad EAS exome

AF:

0.427

Gnomad SAS exome

AF:

0.494

Gnomad FIN exome

AF:

0.481

Gnomad NFE exome

AF:

0.495

Gnomad OTH exome

AF:

0.510

GnomAD4 exome

AF:

0.493

AC:

720199

AN:

1461712

Hom.:

179006

Cov.:

AF XY:

0.493

AC XY:

358325

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.686

Gnomad4 AMR exome

AF:

0.561

Gnomad4 ASJ exome

AF:

0.536

Gnomad4 EAS exome

AF:

0.464

Gnomad4 SAS exome

AF:

0.493

Gnomad4 FIN exome

AF:

0.483

Gnomad4 NFE exome

AF:

0.483

Gnomad4 OTH exome

AF:

0.513

GnomAD4 genome

AF:

0.550

AC:

83516

AN:

151980

Hom.:

23584

Cov.:

AF XY:

0.550

AC XY:

40835

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.677

Gnomad4 AMR

AF:

0.576

Gnomad4 ASJ

AF:

0.539

Gnomad4 EAS

AF:

0.432

Gnomad4 SAS

AF:

0.507

Gnomad4 FIN

AF:

0.484

Gnomad4 NFE

AF:

0.490

Gnomad4 OTH

AF:

0.541

Alfa

AF:

0.510

Hom.:

6487

Bravo

AF:

0.561

TwinsUK

AF:

0.468

AC:

1736

ALSPAC

AF:

0.489

AC:

1883

ESP6500AA

AF:

0.686

AC:

3021

ESP6500EA

AF:

0.489

AC:

4209

ExAC

AF:

0.514

AC:

62416

Asia WGS

AF:

0.502

AC:

1747

AN:

3478

EpiCase

AF:

0.503

EpiControl

AF:

0.513

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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: MAF -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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 85% of patients studied by a panel of primary immunodeficiencies. Number of patients: 75. Only high quality variants are reported. -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 25495765, 21196704, 23534907, 25853559, 19005244) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Epidermodysplasia verruciformis, susceptibility to, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Epidermodysplasia verruciformis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.034

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

8.3

DANN

Benign

0.79

DEOGEN2

Benign

0.013

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.32

T;T

MetaRNN

Benign

0.0000094

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.6

N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.50

PROVEAN

Benign

4.5

N;.

REVEL

Benign

0.072

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.11

MPC

0.20

ClinPred

0.0028

GERP RS

4.7

Varity_R

0.11

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