17-78134906-G-T

Variant names:

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.1024G>T(p.Gly342Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0289 in 1,614,058 control chromosomes in the GnomAD database, including 832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G342V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 38 hom., cov: 33)

Exomes 𝑓: 0.030 ( 794 hom. )

Consequence

TMC8
NM_152468.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.94

Publications

8 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=0.0032699704).

BP6

Variant 17-78134906-G-T is Benign according to our data. Variant chr17-78134906-G-T is described in ClinVar as Benign. ClinVar VariationId is 456020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0553 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.1024G>T	p.Gly342Trp	missense	Exon 9 of 16	NP_689681.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMC8	ENST00000318430.10	TSL:1 MANE Select	c.1024G>T	p.Gly342Trp	missense	Exon 9 of 16	ENSP00000325561.4
TMC8	ENST00000589691.1	TSL:1	c.355G>T	p.Gly119Trp	missense	Exon 8 of 15	ENSP00000467482.1
TMC8	ENST00000972441.1		c.1069G>T	p.Gly357Trp	missense	Exon 9 of 16	ENSP00000642500.1

Frequencies

GnomAD3 genomes

AF:

0.0189

AC:

2882

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00572

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.0418

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0612

Gnomad FIN

AF:

0.0115

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0271

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.0246

AC:

6172

AN:

251158

AF XY:

0.0279

show subpopulations

Gnomad AFR exome

AF:

0.00573

Gnomad AMR exome

AF:

0.00697

Gnomad ASJ exome

AF:

0.0437

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0125

Gnomad NFE exome

AF:

0.0284

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0299

AC:

43733

AN:

1461818

Hom.:

794

Cov.:

AF XY:

0.0310

AC XY:

22514

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.00478

AC:

160

AN:

33480

American (AMR)

AF:

0.00727

AC:

325

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0430

AC:

1123

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0568

AC:

4900

AN:

86258

European-Finnish (FIN)

AF:

0.0129

AC:

688

AN:

53364

Middle Eastern (MID)

AF:

0.0203

AC:

117

AN:

5768

European-Non Finnish (NFE)

AF:

0.0312

AC:

34674

AN:

1112000

Other (OTH)

AF:

0.0289

AC:

1743

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

2797

5595

8392

11190

13987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1368

2736

4104

5472

6840

<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:

0.0189

AC:

2878

AN:

152240

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1372

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00571

AC:

237

AN:

41528

American (AMR)

AF:

0.0114

AC:

174

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0418

AC:

145

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5178

South Asian (SAS)

AF:

0.0611

AC:

295

AN:

4832

European-Finnish (FIN)

AF:

0.0115

AC:

122

AN:

10616

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0271

AC:

1845

AN:

67998

Other (OTH)

AF:

0.0156

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

150

300

449

599

749

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0259

Hom.:

168

Bravo

AF:

0.0167

TwinsUK

AF:

0.0299

AC:

111

ALSPAC

AF:

0.0301

AC:

116

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.0290

AC:

249

ExAC

AF:

0.0246

AC:

2989

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0258

EpiControl

AF:

0.0258

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

Pathogenic

0.74

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.049

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.6

PhyloP100

4.9

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.3

REVEL

Benign

0.17

Sift

Uncertain

0.029

Sift4G

Uncertain

0.026

Polyphen

1.0

Vest4

0.27

MPC

0.74

ClinPred

0.015

GERP RS

4.5

Varity_R

0.12

gMVP

0.65

Mutation Taster

=96/4

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