rs9425

Variant names:

• chr10-104031597-C-T
• rs9425
• NM_000494.4:c.*638G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000494.4(COL17A1):​c.*638G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 153,578 control chromosomes in the GnomAD database, including 3,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3141 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12 hom.)
• Consequence: COL17A1 NM_000494.4 3_prime_UTR
• Scores: Splicing: ADA: 0.00001952
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.97
• Publications: 8 publications found

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]

COL17A1 Gene-Disease associations (from GenCC):

• epithelial recurrent erosion dystrophy

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• epidermolysis bullosa, junctional 4, intermediate

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• generalized junctional epidermolysis bullosa non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• late-onset junctional epidermolysis bullosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• localized junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-104031597-C-T is Benign according to our data. Variant chr10-104031597-C-T is described in ClinVar as [Benign]. Clinvar id is 298673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL17A1	NM_000494.4	c.*638G>A		3_prime_UTR_variant	Exon 56 of 56	ENST00000648076.2	NP_000485.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL17A1	ENST00000648076.2	c.*638G>A		3_prime_UTR_variant	Exon 56 of 56		NM_000494.4	ENSP00000497653.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29777 AN: 151898 Hom.: 3129 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.0923

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.188

GnomAD4 exome AF: 0.119 AC: 186 AN: 1562 Hom.: 12 Cov.: 0 AF XY: 0.135 AC XY: 109 AN XY: 810

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.118 AC: 36 AN: 306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.0455 AC: 1 AN: 22

South Asian (SAS) AF: 0.160 AC: 23 AN: 144

European-Finnish (FIN) AF: 0.500 AC: 2 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.116 AC: 119 AN: 1030

Other (OTH) AF: 0.100 AC: 5 AN: 50

GnomAD4 genome AF: 0.196 AC: 29835 AN: 152016 Hom.: 3141 Cov.: 32 AF XY: 0.198 AC XY: 14724 AN XY: 74294

African (AFR) AF: 0.258 AC: 10684 AN: 41452

American (AMR) AF: 0.169 AC: 2588 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 453 AN: 3472

East Asian (EAS) AF: 0.0926 AC: 478 AN: 5164

South Asian (SAS) AF: 0.172 AC: 828 AN: 4816

European-Finnish (FIN) AF: 0.232 AC: 2442 AN: 10536

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11666 AN: 67978

Other (OTH) AF: 0.186 AC: 391 AN: 2106

Alfa AF: 0.176 Hom.: 9283

Bravo AF: 0.195

Asia WGS AF: 0.152 AC: 528 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.25
DANN	Benign	0.50
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs9425; hg19: chr10-105791355;