rs121912773

Positions:

• chr10-104053072-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000494.4(COL17A1):​c.1898G>A​(p.Gly633Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL17A1 NM_000494.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.22

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 10-104053072-C-T is Pathogenic according to our data. Variant chr10-104053072-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17657.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL17A1	NM_000494.4	c.1898G>A	p.Gly633Asp	missense_variant	23/56	ENST00000648076.2	NP_000485.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL17A1	ENST00000648076.2	c.1898G>A	p.Gly633Asp	missense_variant	23/56		NM_000494.4	ENSP00000497653.1
COL17A1	ENST00000369733.8	c.1898G>A	p.Gly633Asp	missense_variant	22/51	5		ENSP00000358748.3
COL17A1	ENST00000650263.1	c.*38G>A		downstream_gene_variant				ENSP00000497850.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Epidermolysis bullosa, junctional 4, intermediate Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	.;D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;.;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.8	H;H;H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.3	D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.97
MutPred		1.0		Loss of methylation at R632 (P = 0.043);Loss of methylation at R632 (P = 0.043);Loss of methylation at R632 (P = 0.043);
MVP		0.94
MPC		0.085
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.96

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

Other links and lift over

dbSNP: rs121912773; hg19: chr10-105812830;