rs560335891

Variant names:

• chr10-104031858-C-T
• rs560335891
• NM_000494.4:c.*377G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000494.4(COL17A1):​c.*377G>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 0.000813 in 297,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: COL17A1 NM_000494.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0100
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000951 (137/144064) while in subpopulation AFR AF = 0.00199 (75/37600). AF 95% confidence interval is 0.00163. There are 0 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL17A1	NM_000494.4	c.*377G>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.*377G>A		3_prime_UTR_variant	Exon 56 of 56		NM_000494.4	ENSP00000497653.1

Frequencies

GnomAD3 genomes AF: 0.000952 AC: 137 AN: 143976 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000543

Gnomad ASJ AF: 0.00648

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000201

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000425

Gnomad OTH AF: 0.00101

GnomAD4 exome AF: 0.000684 AC: 105 AN: 153430 Hom.: 0 Cov.: 0 AF XY: 0.000591 AC XY: 48 AN XY: 81220

African (AFR) AF: 0.000555 AC: 3 AN: 5406

American (AMR) AF: 0.000565 AC: 4 AN: 7080

Ashkenazi Jewish (ASJ) AF: 0.00422 AC: 18 AN: 4270

East Asian (EAS) AF: 0.000115 AC: 1 AN: 8722

South Asian (SAS) AF: 0.000238 AC: 5 AN: 20996

European-Finnish (FIN) AF: 0.000160 AC: 1 AN: 6252

Middle Eastern (MID) AF: 0.00159 AC: 1 AN: 628

European-Non Finnish (NFE) AF: 0.000686 AC: 63 AN: 91796

Other (OTH) AF: 0.00109 AC: 9 AN: 8280

GnomAD4 genome AF: 0.000951 AC: 137 AN: 144064 Hom.: 0 Cov.: 32 AF XY: 0.000925 AC XY: 65 AN XY: 70304

African (AFR) AF: 0.00199 AC: 75 AN: 37600

American (AMR) AF: 0.000542 AC: 8 AN: 14752

Ashkenazi Jewish (ASJ) AF: 0.00648 AC: 22 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4352

European-Finnish (FIN) AF: 0.000201 AC: 2 AN: 9944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000425 AC: 28 AN: 65808

Other (OTH) AF: 0.00101 AC: 2 AN: 1990

Alfa AF: 0.000832 Hom.: 0

Bravo AF: 0.000933

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Junctional epidermolysis bullosa, non-Herlitz type Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.9
DANN	Benign	0.65
PhyloP100		0.010

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: rs560335891; hg19: chr10-105791616;