17-78134966-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_152468.5(TMC8):​c.1084G>T​(p.Glu362*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TMC8
NM_152468.5 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 8.28
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-78134966-G-T is Pathogenic according to our data. Variant chr17-78134966-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 4747.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-78134966-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMC8NM_152468.5 linkc.1084G>T p.Glu362* stop_gained Exon 9 of 16 ENST00000318430.10 NP_689681.2 Q8IU68-1A0A024R8N8B3KXZ8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMC8ENST00000318430.10 linkc.1084G>T p.Glu362* stop_gained Exon 9 of 16 1 NM_152468.5 ENSP00000325561.4 Q8IU68-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251314
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135884
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461758
Hom.:
0
Cov.:
34
AF XY:
0.00000413
AC XY:
3
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Epidermodysplasia verruciformis Pathogenic:1
Oct 26, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with epidermodysplasia verruciformis (PMID: 12426567). ClinVar contains an entry for this variant (Variation ID: 4747). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu362*) in the TMC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMC8 are known to be pathogenic (PMID: 12426567, 22158547). -

Epidermodysplasia verruciformis, susceptibility to, 2 Other:1
Dec 01, 2002
OMIM
Significance: risk factor
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
42
DANN
Uncertain
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.93
D
Vest4
0.90
GERP RS
4.5

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908330; hg19: chr17-76131047; API