rs4918079

Variant names:

• chr10-104041495-G-A
• rs4918079
• NM_000494.4:c.2595C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-104041495-G-A
• chr10-104041495-G-C
• chr10-104041495-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000494.4(COL17A1):​c.2595C>T​(p.Arg865Arg) 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:7
• Conservation: PhyloP100: -0.211
• Publications: 26 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 -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 VariationId is 256269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000494.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL17A1	NM_000494.4	MANE Select	c.2595C>T	p.Arg865Arg	synonymous	Exon 37 of 56	NP_000485.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL17A1	ENST00000648076.2	MANE Select	c.2595C>T	p.Arg865Arg	synonymous	Exon 37 of 56	ENSP00000497653.1
	COL17A1	ENST00000369733.8	TSL:5	c.2595C>T	p.Arg865Arg	synonymous	Exon 36 of 51	ENSP00000358748.3

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

GnomAD2 exomes AF: 0.776 AC: 193833 AN: 249860 AF XY: 0.778

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 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

African (AFR) AF: 0.476 AC: 15895 AN: 33396

American (AMR) AF: 0.782 AC: 34898 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 20970 AN: 26106

East Asian (EAS) AF: 0.749 AC: 29715 AN: 39686

South Asian (SAS) AF: 0.714 AC: 61462 AN: 86136

European-Finnish (FIN) AF: 0.771 AC: 41133 AN: 53384

Middle Eastern (MID) AF: 0.774 AC: 4456 AN: 5758

European-Non Finnish (NFE) AF: 0.835 AC: 926938 AN: 1110346

Other (OTH) AF: 0.790 AC: 47646 AN: 60306

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

African (AFR) AF: 0.494 AC: 20409 AN: 41320

American (AMR) AF: 0.784 AC: 11977 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 2844 AN: 3466

East Asian (EAS) AF: 0.775 AC: 3967 AN: 5116

South Asian (SAS) AF: 0.697 AC: 3346 AN: 4802

European-Finnish (FIN) AF: 0.769 AC: 8140 AN: 10584

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.830 AC: 56405 AN: 67946

Other (OTH) AF: 0.745 AC: 1570 AN: 2108

Alfa AF: 0.784 Hom.: 39232

Bravo AF: 0.716

Asia WGS AF: 0.693 AC: 2405 AN: 3476

EpiCase AF: 0.832

EpiControl AF: 0.827

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Junctional epidermolysis bullosa, non-Herlitz type (2)
-	-	1	Epithelial recurrent erosion dystrophy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.93
DANN	Benign	0.63
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4918079; hg19: chr10-105801253; COSMIC: COSV62226758;