rs752317971

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

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.49
Variant links:
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]

Genome browser will be placed here

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
COL17A1NM_000494.4 linkuse as main transcriptc.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
COL17A1ENST00000648076.2 linkuse as main transcriptc.2407G>T p.Gly803Ter stop_gained 34/56 NM_000494.4 ENSP00000497653 A2Q9UMD9-1
COL17A1ENST00000369733.8 linkuse as main transcriptc.2407G>T p.Gly803Ter stop_gained 33/515 ENSP00000358748 P4Q9UMD9-2

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461890
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727248
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000278
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 submitterclinical testingGeneDxSep 21, 2023Observed 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 submitterclinical testingEurofins Ntd Llc (ga)Nov 03, 2016- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 10, 2024This 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 submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017The 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 providedliterature onlyOMIMMar 29, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
40
DANN
Uncertain
0.99
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.87
D
MutationTaster
Benign
1.0
A;A
Vest4
0.74
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.15
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: rs752317971; hg19: chr10-105803610; API