10-104039114-T-C

Variant names:

• chr10-104039114-T-C
• rs2274100
• NM_000494.4:c.2904A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000494.4(COL17A1):​c.2904A>G​(p.Pro968Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,613,702 control chromosomes in the GnomAD database, including 529,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P968P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.73 (41716 hom., cov: 31)
  • Exomes 𝑓: 0.81 (488280 hom.)
• Consequence: COL17A1 NM_000494.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.712
• Publications: 23 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 10-104039114-T-C is Benign according to our data. Variant chr10-104039114-T-C is described in CliVar as Benign. Clinvar id is 256271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104039114-T-C is described in CliVar as Benign. Clinvar id is 256271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104039114-T-C is described in CliVar as Benign. Clinvar id is 256271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104039114-T-C is described in CliVar as Benign. Clinvar id is 256271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104039114-T-C is described in CliVar as Benign. Clinvar id is 256271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104039114-T-C is described in CliVar as Benign. Clinvar id is 256271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104039114-T-C is described in CliVar as Benign. Clinvar id is 256271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104039114-T-C is described in CliVar as Benign. Clinvar id is 256271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104039114-T-C is described in CliVar as Benign. Clinvar id is 256271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104039114-T-C is described in CliVar as Benign. Clinvar id is 256271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104039114-T-C is described in CliVar as Benign. Clinvar id is 256271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.712 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL17A1	NM_000494.4	c.2904A>G	p.Pro968Pro	synonymous_variant	Exon 44 of 56	ENST00000648076.2	NP_000485.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL17A1	ENST00000648076.2	c.2904A>G	p.Pro968Pro	synonymous_variant	Exon 44 of 56		NM_000494.4	ENSP00000497653.1
COL17A1	ENST00000369733.8	c.2769A>G	p.Pro923Pro	synonymous_variant	Exon 40 of 51	5		ENSP00000358748.3

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110457 AN: 151970 Hom.: 41720 Cov.: 31

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.787

Gnomad ASJ AF: 0.832

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.709

Gnomad FIN AF: 0.771

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.833

Gnomad OTH AF: 0.756

GnomAD2 exomes AF: 0.782 AC: 196539 AN: 251416 AF XY: 0.784

Gnomad AFR exome AF: 0.493

Gnomad AMR exome AF: 0.788

Gnomad ASJ exome AF: 0.818

Gnomad EAS exome AF: 0.804

Gnomad FIN exome AF: 0.770

Gnomad NFE exome AF: 0.831

Gnomad OTH exome AF: 0.807

GnomAD4 exome AF: 0.815 AC: 1190902 AN: 1461614 Hom.: 488280 Cov.: 54 AF XY: 0.813 AC XY: 591013 AN XY: 727134

African (AFR) AF: 0.481 AC: 16108 AN: 33472

American (AMR) AF: 0.786 AC: 35172 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.818 AC: 21390 AN: 26136

East Asian (EAS) AF: 0.777 AC: 30829 AN: 39700

South Asian (SAS) AF: 0.727 AC: 62698 AN: 86250

European-Finnish (FIN) AF: 0.773 AC: 41282 AN: 53412

Middle Eastern (MID) AF: 0.779 AC: 4486 AN: 5762

European-Non Finnish (NFE) AF: 0.837 AC: 930944 AN: 1111772

Other (OTH) AF: 0.795 AC: 47993 AN: 60390

GnomAD4 genome AF: 0.726 AC: 110477 AN: 152088 Hom.: 41716 Cov.: 31 AF XY: 0.726 AC XY: 53953 AN XY: 74346

African (AFR) AF: 0.499 AC: 20673 AN: 41466

American (AMR) AF: 0.787 AC: 12031 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.832 AC: 2887 AN: 3472

East Asian (EAS) AF: 0.790 AC: 4068 AN: 5152

South Asian (SAS) AF: 0.710 AC: 3421 AN: 4820

European-Finnish (FIN) AF: 0.771 AC: 8153 AN: 10580

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.833 AC: 56630 AN: 67992

Other (OTH) AF: 0.750 AC: 1580 AN: 2108

Alfa AF: 0.796 Hom.: 73814

Bravo AF: 0.720

Asia WGS AF: 0.703 AC: 2444 AN: 3478

EpiCase AF: 0.835

EpiControl AF: 0.830

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Mar 03, 2015

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Junctional epidermolysis bullosa, non-Herlitz type Benign:2

Jan 13, 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. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epithelial recurrent erosion dystrophy Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.46
DANN	Benign	0.38
PhyloP100		-0.71
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: rs2274100; hg19: chr10-105798872; COSMIC: COSV62226747;