rs11651675

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152468.5(TMC8):c.1501G>A(p.Val501Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0387 in 1,613,810 control chromosomes in the GnomAD database, including 1,473 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 110 hom., cov: 33)

Exomes 𝑓: 0.039 ( 1363 hom. )

Consequence

TMC8
NM_152468.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.59

Publications

13 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021557808).

BP6

Variant 17-78138156-G-A is Benign according to our data. Variant chr17-78138156-G-A is described in ClinVar as Benign. ClinVar VariationId is 456022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0895 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152468.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMC8	NM_152468.5	MANE Select	c.1501G>A	p.Val501Ile	missense	Exon 12 of 16	NP_689681.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMC8	ENST00000318430.10	TSL:1 MANE Select	c.1501G>A	p.Val501Ile	missense	Exon 12 of 16	ENSP00000325561.4
TMC8	ENST00000589691.1	TSL:1	c.832G>A	p.Val278Ile	missense	Exon 11 of 15	ENSP00000467482.1
TMC8	ENST00000972441.1		c.1546G>A	p.Val516Ile	missense	Exon 12 of 16	ENSP00000642500.1

Frequencies

GnomAD3 genomes

AF:

0.0331

AC:

5027

AN:

151972

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0335

Gnomad ASJ

AF:

0.0444

Gnomad EAS

AF:

0.00810

Gnomad SAS

AF:

0.0966

Gnomad FIN

AF:

0.0205

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0376

Gnomad OTH

AF:

0.0399

GnomAD2 exomes

AF:

0.0378

AC:

9488

AN:

250886

AF XY:

0.0411

show subpopulations

Gnomad AFR exome

AF:

0.0234

Gnomad AMR exome

AF:

0.0256

Gnomad ASJ exome

AF:

0.0400

Gnomad EAS exome

AF:

0.00935

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.0379

Gnomad OTH exome

AF:

0.0404

GnomAD4 exome

AF:

0.0393

AC:

57411

AN:

1461720

Hom.:

1363

Cov.:

AF XY:

0.0408

AC XY:

29697

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0228

AC:

762

AN:

33480

American (AMR)

AF:

0.0249

AC:

1114

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0391

AC:

1022

AN:

26134

East Asian (EAS)

AF:

0.00370

AC:

147

AN:

39700

South Asian (SAS)

AF:

0.0843

AC:

7270

AN:

86258

European-Finnish (FIN)

AF:

0.0214

AC:

1141

AN:

53280

Middle Eastern (MID)

AF:

0.0667

AC:

385

AN:

5768

European-Non Finnish (NFE)

AF:

0.0386

AC:

42890

AN:

1111992

Other (OTH)

AF:

0.0444

AC:

2680

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

3935

7870

11806

15741

19676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1632

3264

4896

6528

8160

<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:

0.0331

AC:

5033

AN:

152090

Hom.:

110

Cov.:

AF XY:

0.0334

AC XY:

2480

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0231

AC:

960

AN:

41484

American (AMR)

AF:

0.0335

AC:

512

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0444

AC:

154

AN:

3470

East Asian (EAS)

AF:

0.00812

AC:

AN:

5172

South Asian (SAS)

AF:

0.0967

AC:

465

AN:

4808

European-Finnish (FIN)

AF:

0.0205

AC:

217

AN:

10598

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0376

AC:

2554

AN:

67968

Other (OTH)

AF:

0.0413

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

253

505

758

1010

1263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0354

Hom.:

442

Bravo

AF:

0.0315

TwinsUK

AF:

0.0307

AC:

114

ALSPAC

AF:

0.0415

AC:

160

ESP6500AA

AF:

0.0222

AC:

ESP6500EA

AF:

0.0386

AC:

332

ExAC

AF:

0.0382

AC:

4644

Asia WGS

AF:

0.0590

AC:

203

AN:

3478

EpiCase

AF:

0.0412

EpiControl

AF:

0.0434

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Epidermodysplasia verruciformis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.0080

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0032

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0022

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.44

PhyloP100

-1.6

PrimateAI

Benign

0.32

PROVEAN

Benign

0.17

REVEL

Benign

0.043

Sift

Benign

0.54

Sift4G

Benign

0.58

Polyphen

0.0040

Vest4

0.033

MPC

0.13

ClinPred

0.0022

GERP RS

-6.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.063

Mutation Taster

=97/3

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over