17-78138747-C-A

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.1823+15C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,602,978 control chromosomes in the GnomAD database, including 254,998 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 30250 hom., cov: 34)

Exomes 𝑓: 0.55 ( 224748 hom. )

Consequence

TMC8
NM_152468.5 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.16

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 (BayesDel_noAF=-0.84).

BP6

Variant 17-78138747-C-A is Benign according to our data. Variant chr17-78138747-C-A is described in ClinVar as Benign. ClinVar VariationId is 403549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5 link	c.1823+15C>A		intron_variant	Intron 14 of 15	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.1823+15C>A		intron_variant	Intron 14 of 15	1	NM_152468.5	ENSP00000325561.4		Q8IU68-1

Frequencies

GnomAD3 genomes

AF:

0.622

AC:

94523

AN:

152028

Hom.:

30191

Cov.:

show subpopulations

Gnomad AFR

AF:

0.756

Gnomad AMI

AF:

0.594

Gnomad AMR

AF:

0.642

Gnomad ASJ

AF:

0.648

Gnomad EAS

AF:

0.437

Gnomad SAS

AF:

0.548

Gnomad FIN

AF:

0.597

Gnomad MID

AF:

0.741

Gnomad NFE

AF:

0.557

Gnomad OTH

AF:

0.622

GnomAD2 exomes

AF:

0.580

AC:

140372

AN:

241890

AF XY:

0.575

show subpopulations

Gnomad AFR exome

AF:

0.762

Gnomad AMR exome

AF:

0.645

Gnomad ASJ exome

AF:

0.644

Gnomad EAS exome

AF:

0.440

Gnomad FIN exome

AF:

0.589

Gnomad NFE exome

AF:

0.562

Gnomad OTH exome

AF:

0.590

GnomAD4 exome

AF:

0.554

AC:

803419

AN:

1450832

Hom.:

224748

Cov.:

AF XY:

0.554

AC XY:

399931

AN XY:

722072

show subpopulations

African (AFR)

AF:

0.765

AC:

25601

AN:

33452

American (AMR)

AF:

0.641

AC:

28625

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.646

AC:

16868

AN:

26104

East Asian (EAS)

AF:

0.448

AC:

17785

AN:

39664

South Asian (SAS)

AF:

0.539

AC:

46496

AN:

86244

European-Finnish (FIN)

AF:

0.582

AC:

24982

AN:

42952

Middle Eastern (MID)

AF:

0.689

AC:

3969

AN:

5762

European-Non Finnish (NFE)

AF:

0.544

AC:

604394

AN:

1111688

Other (OTH)

AF:

0.575

AC:

34699

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

21488

42975

64463

85950

107438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17074

34148

51222

68296

85370

<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:

0.622

AC:

94646

AN:

152146

Hom.:

30250

Cov.:

AF XY:

0.622

AC XY:

46288

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.756

AC:

31395

AN:

41506

American (AMR)

AF:

0.642

AC:

9828

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.648

AC:

2247

AN:

3470

East Asian (EAS)

AF:

0.437

AC:

2253

AN:

5158

South Asian (SAS)

AF:

0.549

AC:

2650

AN:

4826

European-Finnish (FIN)

AF:

0.597

AC:

6325

AN:

10600

Middle Eastern (MID)

AF:

0.738

AC:

217

AN:

294

European-Non Finnish (NFE)

AF:

0.557

AC:

37867

AN:

67972

Other (OTH)

AF:

0.627

AC:

1322

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1845

3689

5534

7378

9223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

764

1528

2292

3056

3820

<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:

0.594

Hom.:

64521

Bravo

AF:

0.633

Asia WGS

AF:

0.532

AC:

1850

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 88% of patients studied by a panel of primary immunodeficiencies. Number of patients: 77. Only high quality variants are reported. -

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Epidermodysplasia verruciformis, susceptibility to, 2

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epidermodysplasia verruciformis

Benign:1

Feb 03, 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

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.11

(source)

DANN

Benign

0.62

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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