rs4918079

chr10-104041495-G-Achr10-104041495-G-Cchr10-104041495-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000494.4(COL17A1):c.2595C>T(p.Arg865=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,611,580 control chromosomes in the GnomAD database, including 524,077 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (41192 hom., cov: 32)
  • Exomes 𝑓: 0.81 (482885 hom.)
• Consequence: COL17A1 NM_000494.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.211

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 10-104041495-G-A is Benign according to our data. Variant chr10-104041495-G-A is described in ClinVar as [Benign]. Clinvar id is 256269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104041495-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.211 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL17A1	NM_000494.4	c.2595C>T	p.Arg865=	synonymous_variant	37/56	ENST00000648076.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL17A1	ENST00000648076.2	c.2595C>T	p.Arg865=	synonymous_variant	37/56		NM_000494.4	A2
COL17A1	ENST00000369733.8	c.2595C>T	p.Arg865=	synonymous_variant	36/51	5		P4

Frequencies

GnomAD3 genomes AF: 0.723 AC: 109670 AN: 151710 Hom.: 41198 Cov.: 32

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.821

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.830

Gnomad OTH AF: 0.751

GnomAD3 exomes AF: 0.776 AC: 193833 AN: 249860 Hom.: 76270 AF XY: 0.778 AC XY: 105251 AN XY: 135342

Gnomad AFR exome AF: 0.487

Gnomad AMR exome AF: 0.783

Gnomad ASJ exome AF: 0.800

Gnomad EAS exome AF: 0.788

Gnomad SAS exome AF: 0.709

Gnomad FIN exome AF: 0.768

Gnomad NFE exome AF: 0.828

Gnomad OTH exome AF: 0.803

GnomAD4 exome AF: 0.810 AC: 1183113 AN: 1459748 Hom.: 482885 Cov.: 43 AF XY: 0.808 AC XY: 587004 AN XY: 726238

Gnomad4 AFR exome AF: 0.476

Gnomad4 AMR exome AF: 0.782

Gnomad4 ASJ exome AF: 0.803

Gnomad4 EAS exome AF: 0.749

Gnomad4 SAS exome AF: 0.714

Gnomad4 FIN exome AF: 0.771

Gnomad4 NFE exome AF: 0.835

Gnomad4 OTH exome AF: 0.790

GnomAD4 genome AF: 0.722 AC: 109691 AN: 151832 Hom.: 41192 Cov.: 32 AF XY: 0.722 AC XY: 53572 AN XY: 74200

Gnomad4 AFR AF: 0.494

Gnomad4 AMR AF: 0.784

Gnomad4 ASJ AF: 0.821

Gnomad4 EAS AF: 0.775

Gnomad4 SAS AF: 0.697

Gnomad4 FIN AF: 0.769

Gnomad4 NFE AF: 0.830

Gnomad4 OTH AF: 0.745

Alfa AF: 0.786 Hom.: 29173

Bravo AF: 0.716

Asia WGS AF: 0.693 AC: 2405 AN: 3476

EpiCase AF: 0.832

EpiControl AF: 0.827

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Junctional epidermolysis bullosa, non-Herlitz type Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24668667) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Epithelial recurrent erosion dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	0.93
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4918079; hg19: chr10-105801253; COSMIC: COSV62226758;