rs752317971
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000494.4(COL17A1):c.2407G>T(p.Gly803Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000434 in 1,614,070 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: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
COL17A1
NM_000494.4 stop_gained
NM_000494.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.49
Genes affected
COL17A1 (HGNC:2194): (collagen type XVII alpha 1 chain) This gene encodes the alpha chain of type XVII collagen. Unlike most collagens, collagen XVII is a transmembrane protein. Collagen XVII is a structural component of hemidesmosomes, multiprotein complexes at the dermal-epidermal basement membrane zone that mediate adhesion of keratinocytes to the underlying membrane. Mutations in this gene are associated with both generalized atrophic benign and junctional epidermolysis bullosa. Two homotrimeric forms of type XVII collagen exist. The full length form is the transmembrane protein. A soluble form, referred to as either ectodomain or LAD-1, is generated by proteolytic processing of the full length form. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 10-104043852-C-A is Pathogenic according to our data. Variant chr10-104043852-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 298713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104043852-C-A is described in Lovd as [Likely_pathogenic]. Variant chr10-104043852-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL17A1 | NM_000494.4 | c.2407G>T | p.Gly803Ter | stop_gained | 34/56 | ENST00000648076.2 | NP_000485.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL17A1 | ENST00000648076.2 | c.2407G>T | p.Gly803Ter | stop_gained | 34/56 | NM_000494.4 | ENSP00000497653 | A2 | ||
COL17A1 | ENST00000369733.8 | c.2407G>T | p.Gly803Ter | stop_gained | 33/51 | 5 | ENSP00000358748 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727248
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2023 | Observed with a second COL17A1 variant on the opposite allele (in trans) in patients with epidermolysis bullosa referred for genetic testing at GeneDx and in published literature (Darling et al.,1997; Hoffmann et al., 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12558632, 30673110, 9077475, 30761300, 21357940) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 03, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 10, 2024 | This sequence change creates a premature translational stop signal (p.Gly803*) in the COL17A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL17A1 are known to be pathogenic (PMID: 16473856, 17344927, 20301304, 21357940, 24319098). This variant is present in population databases (rs752317971, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with junctional epidermolysis bullosa (PMID: 9077475). ClinVar contains an entry for this variant (Variation ID: 298713). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Junctional epidermolysis bullosa, non-Herlitz type Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The COL17A1 c.2407G>T (p.Gly803Ter) variant is a stop-gained variant predicted to result in premature truncation of the protein. The p.Gly803Ter variant has been reported in two studies in which it is found in a total of six patients with junctional epidermolysis bullosa, including in one in a homozygous state, in four in a compound heterozygous state, and in one in a heterozygous state in whom a second variant was not identified (Darling et al. 1997; Kiritsi et al. 2011). The variant was also detected in a heterozygous state in one unaffected father of one of the compound heterozygotes. The homozygous individual showed severely reduced staining for type XVII collagen in the skin. The p.Gly803Ter variant was absent from one control individual and is reported at a frequency of 0.00001 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on one allele only in a region of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Gly803Ter variant is classified as pathogenic for junctional epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Epidermolysis bullosa, junctional 4, intermediate Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 29, 2022 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
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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