10-104032171-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000494.4(COL17A1):c.*64G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,320,836 control chromosomes in the GnomAD database, including 23,214 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4541 hom., cov: 32)
  • Exomes 𝑓: 0.17 (18673 hom.)
• Consequence: COL17A1 NM_000494.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.335

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-104032171-C-G is Benign according to our data. Variant chr10-104032171-C-G is described in ClinVar as [Benign]. Clinvar id is 298678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL17A1	NM_000494.4	c.*64G>C		3_prime_UTR_variant	56/56	ENST00000648076.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL17A1	ENST00000648076.2	c.*64G>C		3_prime_UTR_variant	56/56		NM_000494.4	A2
COL17A1	ENST00000369733.8	c.*64G>C		3_prime_UTR_variant	51/51	5		P4
COL17A1	ENST00000433822.1	c.*31+33G>C		intron_variant		5
COL17A1	ENST00000647647.1	c.*628G>C		3_prime_UTR_variant, NMD_transcript_variant	5/5

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34516 AN: 152046 Hom.: 4528 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.0966

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.216

GnomAD4 exome AF: 0.174 AC: 203039 AN: 1168672 Hom.: 18673 Cov.: 16 AF XY: 0.174 AC XY: 103523 AN XY: 595330

Gnomad4 AFR exome AF: 0.368

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.147

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.180

GnomAD4 genome AF: 0.227 AC: 34583 AN: 152164 Hom.: 4541 Cov.: 32 AF XY: 0.227 AC XY: 16911 AN XY: 74394

Gnomad4 AFR AF: 0.362

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.0969

Gnomad4 SAS AF: 0.179

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.215

Alfa AF: 0.211 Hom.: 542

Bravo AF: 0.231

Asia WGS AF: 0.163 AC: 566 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

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.1
Dann	Benign	0.55

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: rs805687; hg19: chr10-105791929;