10-104031597-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -1.97

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 Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
COL17A1	NM_000494.4	c.*638G>A		3_prime_UTR_variant	56/56	ENST00000648076.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL17A1	ENST00000648076.2	c.*638G>A		3_prime_UTR_variant	56/56		NM_000494.4	A2
COL17A1	ENST00000369733.8	c.*638G>A		3_prime_UTR_variant	51/51	5		P4
COL17A1	ENST00000433822.1	c.*32-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
COL17A1	ENST00000647647.1	c.*1202G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0455

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.100

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

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.0926

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.186

Alfa AF: 0.172 Hom.: 3932

Bravo AF: 0.195

Asia WGS AF: 0.152 AC: 528 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.25
Dann	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs9425; hg19: chr10-105791355;