rs797045084

chr10-104043575-GACCCCTCTGAAA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000494.4(COL17A1):c.2435-6_2440del variant causes a splice acceptor, coding sequence, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL17A1 NM_000494.4 splice_acceptor, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.97

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.017801514 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of 27, new splice context is: atcgatgctcactgtcccAGgcc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-104043575-GACCCCTCTGAAA-G is Pathogenic according to our data. Variant chr10-104043575-GACCCCTCTGAAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL17A1	NM_000494.4	c.2435-6_2440del		splice_acceptor_variant, coding_sequence_variant, intron_variant	35/56	ENST00000648076.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL17A1	ENST00000648076.2	c.2435-6_2440del		splice_acceptor_variant, coding_sequence_variant, intron_variant	35/56		NM_000494.4	A2
COL17A1	ENST00000369733.8	c.2435-6_2440del		splice_acceptor_variant, coding_sequence_variant, intron_variant	34/51	5		P4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Junctional epidermolysis bullosa, non-Herlitz type Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 18, 2014

The c.2435-6_2440del variant in COL17A1 has not been previously reported in individuals/any other families with disease. Data from large population studies is insufficient to assess the frequency of this variant. This variant deletes the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Homozygous or compound heterozygous loss of function variants in COL17A1 have been shown to cause junctional epidermolysis bullosa. In summary, although additional studies are required to fully establish its clinical significance, the c.2435-6_2440del variant is likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 04, 2023

This variant results in the deletion of part of exon 35 (c.2435-6_2440del) of the COL17A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL17A1 are known to be pathogenic (PMID: 16473856, 17344927, 20301304, 21357940, 24319098). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL17A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 208569). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045084; hg19: chr10-105803333;