rs139972217

Positions:

chr17-78140913-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_152468.5(TMC8):c.1982C>T(p.Pro661Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,606,402 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 25 hom. )

Consequence

TMC8
NM_152468.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.783

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041273236).

BP6

Variant 17-78140913-C-T is Benign according to our data. Variant chr17-78140913-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456026.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=2, Likely_benign=1}. Variant chr17-78140913-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00354 (539/152352) while in subpopulation AMR AF= 0.00516 (79/15310). AF 95% confidence interval is 0.00432. There are 2 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMC8	NM_152468.5 linkuse as main transcript	c.1982C>T	p.Pro661Leu	missense_variant	16/16	ENST00000318430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMC8	ENST00000318430.10 linkuse as main transcript	c.1982C>T	p.Pro661Leu	missense_variant	16/16	1	NM_152468.5	P2	Q8IU68-1

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

539

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00475

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00340

AC:

786

AN:

230866

Hom.:

AF XY:

0.00326

AC XY:

410

AN XY:

125764

show subpopulations

Gnomad AFR exome

AF:

0.000694

Gnomad AMR exome

AF:

0.00174

Gnomad ASJ exome

AF:

0.000525

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000208

Gnomad FIN exome

AF:

0.00929

Gnomad NFE exome

AF:

0.00494

Gnomad OTH exome

AF:

0.00337

GnomAD4 exome

AF:

0.00397

AC:

5777

AN:

1454050

Hom.:

Cov.:

AF XY:

0.00390

AC XY:

2816

AN XY:

722930

show subpopulations

Gnomad4 AFR exome

AF:

0.000449

Gnomad4 AMR exome

AF:

0.00218

Gnomad4 ASJ exome

AF:

0.000541

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000294

Gnomad4 FIN exome

AF:

0.00908

Gnomad4 NFE exome

AF:

0.00449

Gnomad4 OTH exome

AF:

0.00292

GnomAD4 genome

AF:

0.00354

AC:

539

AN:

152352

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

269

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00516

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00847

Gnomad4 NFE

AF:

0.00475

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00407

Hom.:

Bravo

AF:

0.00316

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000683

AC:

ESP6500EA

AF:

0.00338

AC:

ExAC

AF:

0.00332

AC:

401

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Epidermodysplasia verruciformis, susceptibility to, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

TMC8 NM_152468.4 exon 16 p.Pro661Leu (c.1982C>T): This variant has not been reported in the literature but is present in 0.8% (90/10628) of Finnish alleles as well as in the homozygous state in the European and Latino alleles in the Genome Aggregation Database https://gnomad.broadinstitute.org/variant/17-78140913-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:456026). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Epidermodysplasia verruciformis, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Nov 25, 2020

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

TMC8: BS2 -

TMC8-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Epidermodysplasia verruciformis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

T;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.51

T;T

MetaRNN

Benign

0.0041

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.18

Sift

Uncertain

0.017

D;.

Sift4G

Uncertain

0.015

D;D

Polyphen

0.74

P;.

Vest4

0.22

MVP

0.53

MPC

0.93

ClinPred

0.011

GERP RS

4.0

Varity_R

0.069

gMVP

0.46

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