rs805687

Variant names:

• chr10-104032171-C-G
• rs805687
• NM_000494.4:c.*64G>C

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.*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:3
• Conservation: PhyloP100: -0.335
• 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=-0.87).
• 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 rank	MANE	Protein	UniProt
COL17A1	NM_000494.4	c.*64G>C		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.*64G>C		3_prime_UTR_variant	Exon 56 of 56		NM_000494.4	ENSP00000497653.1

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

African (AFR) AF: 0.368 AC: 10154 AN: 27614

American (AMR) AF: 0.200 AC: 8751 AN: 43788

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3565 AN: 24240

East Asian (EAS) AF: 0.108 AC: 4144 AN: 38282

South Asian (SAS) AF: 0.177 AC: 14174 AN: 80018

European-Finnish (FIN) AF: 0.229 AC: 12019 AN: 52486

Middle Eastern (MID) AF: 0.154 AC: 788 AN: 5112

European-Non Finnish (NFE) AF: 0.166 AC: 140300 AN: 846420

Other (OTH) AF: 0.180 AC: 9144 AN: 50712

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

African (AFR) AF: 0.362 AC: 15037 AN: 41488

American (AMR) AF: 0.183 AC: 2803 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 462 AN: 3470

East Asian (EAS) AF: 0.0969 AC: 502 AN: 5182

South Asian (SAS) AF: 0.179 AC: 863 AN: 4820

European-Finnish (FIN) AF: 0.232 AC: 2453 AN: 10580

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11701 AN: 68018

Other (OTH) AF: 0.215 AC: 453 AN: 2110

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.55
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs805687; hg19: chr10-105791929;