rs12452890

Positions:

chr17-78134989-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000318430.10(TMC8):c.1107G>A(p.Glu369=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,613,796 control chromosomes in the GnomAD database, including 220,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26105 hom., cov: 32)

Exomes 𝑓: 0.51 ( 194160 hom. )

Consequence

TMC8
ENST00000318430.10 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.43

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 17-78134989-G-A is Benign according to our data. Variant chr17-78134989-G-A is described in ClinVar as [Benign]. Clinvar id is 403547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-78134989-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMC8	NM_152468.5 linkuse as main transcript	c.1107G>A	p.Glu369=	synonymous_variant	9/16	ENST00000318430.10	NP_689681.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10 linkuse as main transcript	c.1107G>A	p.Glu369=	synonymous_variant	9/16	1	NM_152468.5	ENSP00000325561	P2	Q8IU68-1

Frequencies

GnomAD3 genomes

AF:

0.578

AC:

87748

AN:

151936

Hom.:

26056

Cov.:

show subpopulations

Gnomad AFR

AF:

0.697

Gnomad AMI

AF:

0.552

Gnomad AMR

AF:

0.606

Gnomad ASJ

AF:

0.607

Gnomad EAS

AF:

0.415

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.575

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.520

Gnomad OTH

AF:

0.573

GnomAD3 exomes

AF:

0.536

AC:

134805

AN:

251286

Hom.:

37129

AF XY:

0.528

AC XY:

71718

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.700

Gnomad AMR exome

AF:

0.618

Gnomad ASJ exome

AF:

0.609

Gnomad EAS exome

AF:

0.414

Gnomad SAS exome

AF:

0.432

Gnomad FIN exome

AF:

0.562

Gnomad NFE exome

AF:

0.525

Gnomad OTH exome

AF:

0.546

GnomAD4 exome

AF:

0.512

AC:

748837

AN:

1461742

Hom.:

194160

Cov.:

AF XY:

0.510

AC XY:

371153

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.708

Gnomad4 AMR exome

AF:

0.614

Gnomad4 ASJ exome

AF:

0.612

Gnomad4 EAS exome

AF:

0.433

Gnomad4 SAS exome

AF:

0.438

Gnomad4 FIN exome

AF:

0.562

Gnomad4 NFE exome

AF:

0.505

Gnomad4 OTH exome

AF:

0.527

GnomAD4 genome

AF:

0.578

AC:

87860

AN:

152054

Hom.:

26105

Cov.:

AF XY:

0.577

AC XY:

42891

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.698

Gnomad4 AMR

AF:

0.607

Gnomad4 ASJ

AF:

0.607

Gnomad4 EAS

AF:

0.414

Gnomad4 SAS

AF:

0.432

Gnomad4 FIN

AF:

0.575

Gnomad4 NFE

AF:

0.520

Gnomad4 OTH

AF:

0.576

Alfa

AF:

0.549

Hom.:

30321

Bravo

AF:

0.590

Asia WGS

AF:

0.462

AC:

1606

AN:

3478

EpiCase

AF:

0.541

EpiControl

AF:

0.540

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	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 83% of patients studied by a panel of primary immunodeficiencies. Number of patients: 73. Only high quality variants are reported. -
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	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 -

not provided

Benign:2Other:1

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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

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

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.3

DANN

Benign

0.60

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