rs1555655146
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001127198.5(TMC6):c.1325_1326insT(p.Thr444AspfsTer57) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L442L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
TMC6
NM_001127198.5 frameshift
NM_001127198.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.71
Genes affected
TMC6 (HGNC:18021): (transmembrane channel like 6) 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 10 transmembrane domains and 2 leucine zipper motifs. [provided by RefSeq, Jul 2008]
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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 17-78121613-C-CA is Pathogenic according to our data. Variant chr17-78121613-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 526234.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC6 | NM_001127198.5 | c.1325_1326insT | p.Thr444AspfsTer57 | frameshift_variant | 11/20 | ENST00000590602.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC6 | ENST00000590602.6 | c.1325_1326insT | p.Thr444AspfsTer57 | frameshift_variant | 11/20 | 2 | NM_001127198.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Epidermodysplasia verruciformis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2017 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TMC6 are known to be pathogenic (PMID: 15042430, 17139267). This variant has not been reported in the literature in individuals with TMC6-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Thr444Aspfs*57) in the TMC6 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at