17-78134866-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.988-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0756 in 1,613,664 control chromosomes in the GnomAD database, including 5,020 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.084 ( 553 hom., cov: 32)

Exomes 𝑓: 0.075 ( 4467 hom. )

Consequence

TMC8
NM_152468.5 splice_region, intron

Scores

Splicing: ADA: 0.00003550

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.18

Publications

10 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=-0.86).

BP6

Variant 17-78134866-G-T is Benign according to our data. Variant chr17-78134866-G-T is described in ClinVar as Benign. ClinVar VariationId is 1098860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5 link	c.988-4G>T		splice_region_variant, intron_variant	Intron 8 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.988-4G>T		splice_region_variant, intron_variant	Intron 8 of 15	1	NM_152468.5	ENSP00000325561.4		Q8IU68-1

Frequencies

GnomAD3 genomes

AF:

0.0837

AC:

12722

AN:

152044

Hom.:

553

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0878

Gnomad AMI

AF:

0.159

Gnomad AMR

AF:

0.0634

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.0909

Gnomad SAS

AF:

0.0667

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.0790

Gnomad OTH

AF:

0.0987

GnomAD2 exomes

AF:

0.0785

AC:

19674

AN:

250726

AF XY:

0.0796

show subpopulations

Gnomad AFR exome

AF:

0.0880

Gnomad AMR exome

AF:

0.0472

Gnomad ASJ exome

AF:

0.143

Gnomad EAS exome

AF:

0.0960

Gnomad FIN exome

AF:

0.0896

Gnomad NFE exome

AF:

0.0807

Gnomad OTH exome

AF:

0.0882

GnomAD4 exome

AF:

0.0747

AC:

109225

AN:

1461502

Hom.:

4467

Cov.:

AF XY:

0.0754

AC XY:

54854

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.0916

AC:

3067

AN:

33480

American (AMR)

AF:

0.0497

AC:

2222

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3756

AN:

26136

East Asian (EAS)

AF:

0.0829

AC:

3291

AN:

39700

South Asian (SAS)

AF:

0.0623

AC:

5371

AN:

86256

European-Finnish (FIN)

AF:

0.0911

AC:

4837

AN:

53090

Middle Eastern (MID)

AF:

0.127

AC:

733

AN:

5752

European-Non Finnish (NFE)

AF:

0.0729

AC:

81061

AN:

1111980

Other (OTH)

AF:

0.0809

AC:

4887

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

6549

13097

19646

26194

32743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2898

5796

8694

11592

14490

<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:

0.0837

AC:

12736

AN:

152162

Hom.:

553

Cov.:

AF XY:

0.0841

AC XY:

6258

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0878

AC:

3644

AN:

41502

American (AMR)

AF:

0.0632

AC:

967

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

491

AN:

3466

East Asian (EAS)

AF:

0.0907

AC:

469

AN:

5170

South Asian (SAS)

AF:

0.0667

AC:

322

AN:

4826

European-Finnish (FIN)

AF:

0.101

AC:

1067

AN:

10600

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0790

AC:

5370

AN:

67980

Other (OTH)

AF:

0.103

AC:

217

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

611

1222

1833

2444

3055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.0719

Hom.:

206

Bravo

AF:

0.0829

Asia WGS

AF:

0.0780

AC:

269

AN:

3478

EpiCase

AF:

0.0920

EpiControl

AF:

0.0872

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epidermodysplasia verruciformis, susceptibility to, 2

Benign:1

May 18, 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

-0.86

CADD

Benign

0.28

(source)

DANN

Benign

0.80

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000036

dbscSNV1_RF

Benign

0.0040

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: 28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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