rs12452890

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_152468.5(TMC8):c.1107G>A(p.Glu369Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,613,796 control chromosomes in the GnomAD database, including 220,265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26105 hom., cov: 32)

Exomes 𝑓: 0.51 ( 194160 hom. )

Consequence

TMC8
NM_152468.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 1.43

Publications

26 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 17-78134989-G-A is Benign according to our data. Variant chr17-78134989-G-A is described in ClinVar as Benign. ClinVar VariationId is 403547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMC8	NM_152468.5 link	c.1107G>A	p.Glu369Glu	synonymous_variant	Exon 9 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.1107G>A	p.Glu369Glu	synonymous_variant	Exon 9 of 16	1	NM_152468.5	ENSP00000325561.4		Q8IU68-1

Frequencies

GnomAD3 genomes

AF:

0.578

AC:

87748

AN:

151936

Hom.:

26056

Cov.:

show subpopulations

Gnomad AFR

AF:

0.697

Gnomad AMI

AF:

0.552

Gnomad AMR

AF:

0.606

Gnomad ASJ

AF:

0.607

Gnomad EAS

AF:

0.415

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.575

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.520

Gnomad OTH

AF:

0.573

GnomAD2 exomes

AF:

0.536

AC:

134805

AN:

251286

AF XY:

0.528

show subpopulations

Gnomad AFR exome

AF:

0.700

Gnomad AMR exome

AF:

0.618

Gnomad ASJ exome

AF:

0.609

Gnomad EAS exome

AF:

0.414

Gnomad FIN exome

AF:

0.562

Gnomad NFE exome

AF:

0.525

Gnomad OTH exome

AF:

0.546

GnomAD4 exome

AF:

0.512

AC:

748837

AN:

1461742

Hom.:

194160

Cov.:

AF XY:

0.510

AC XY:

371153

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.708

AC:

23688

AN:

33478

American (AMR)

AF:

0.614

AC:

27437

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.612

AC:

16002

AN:

26134

East Asian (EAS)

AF:

0.433

AC:

17201

AN:

39700

South Asian (SAS)

AF:

0.438

AC:

37761

AN:

86254

European-Finnish (FIN)

AF:

0.562

AC:

29975

AN:

53360

Middle Eastern (MID)

AF:

0.627

AC:

3613

AN:

5766

European-Non Finnish (NFE)

AF:

0.505

AC:

561318

AN:

1111938

Other (OTH)

AF:

0.527

AC:

31842

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

23655

47310

70965

94620

118275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16238

32476

48714

64952

81190

<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:

0.578

AC:

87860

AN:

152054

Hom.:

26105

Cov.:

AF XY:

0.577

AC XY:

42891

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.698

AC:

28942

AN:

41474

American (AMR)

AF:

0.607

AC:

9268

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.607

AC:

2104

AN:

3466

East Asian (EAS)

AF:

0.414

AC:

2134

AN:

5154

South Asian (SAS)

AF:

0.432

AC:

2079

AN:

4818

European-Finnish (FIN)

AF:

0.575

AC:

6082

AN:

10572

Middle Eastern (MID)

AF:

0.643

AC:

189

AN:

294

European-Non Finnish (NFE)

AF:

0.520

AC:

35343

AN:

67974

Other (OTH)

AF:

0.576

AC:

1216

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1879

3758

5636

7515

9394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

732

1464

2196

2928

3660

<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:

0.554

Hom.:

38199

Bravo

AF:

0.590

Asia WGS

AF:

0.462

AC:

1606

AN:

3478

EpiCase

AF:

0.541

EpiControl

AF:

0.540

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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 -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 83% of patients studied by a panel of primary immunodeficiencies. Number of patients: 73. Only high quality variants are reported. -

not provided

Benign:2Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

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

-0.64

CADD

Benign

4.3

(source)

DANN

Benign

0.60

PhyloP100

1.4

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over