rs139972217

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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. 13/21 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

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

epidermodysplasia verruciformis, susceptibility to, 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
epidermodysplasia verruciformis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMC8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 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 VariationId is 456026.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5 link	c.1982C>T	p.Pro661Leu	missense_variant	Exon 16 of 16	ENST00000318430.10	NP_689681.2	Q8IU68-1A0A024R8N8B3KXZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMC8	ENST00000318430.10 link	c.1982C>T	p.Pro661Leu	missense_variant	Exon 16 of 16	1	NM_152468.5	ENSP00000325561.4		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

GnomAD2 exomes

AF:

0.00340

AC:

786

AN:

230866

AF XY:

0.00326

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 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

African (AFR)

AF:

0.000449

AC:

AN:

33400

American (AMR)

AF:

0.00218

AC:

AN:

43586

Ashkenazi Jewish (ASJ)

AF:

0.000541

AC:

AN:

25864

East Asian (EAS)

AF:

0.00

AC:

AN:

39334

South Asian (SAS)

AF:

0.000294

AC:

AN:

85006

European-Finnish (FIN)

AF:

0.00908

AC:

471

AN:

51864

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00449

AC:

4981

AN:

1109260

Other (OTH)

AF:

0.00292

AC:

175

AN:

60000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

373

745

1118

1490

1863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

344

516

688

860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00354

AC:

539

AN:

152352

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

269

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000842

AC:

AN:

41572

American (AMR)

AF:

0.00516

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00847

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00475

AC:

323

AN:

68022

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00400

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

Mar 30, 2021

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 25, 2020

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TMC8-related disorder

Benign:1

Sep 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

not provided

Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TMC8: BS2 -

Epidermodysplasia verruciformis

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

0.78

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

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over