NM_000494.4:c.2362+195G>T

Variant names:

• chr10-104046552-C-A
• rs805721
• NM_000494.4:c.2362+195G>T

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.2362+195G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 152,028 control chromosomes in the GnomAD database, including 38,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.71 (38439 hom., cov: 31)
• Consequence: COL17A1 NM_000494.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.29
• Publications: 4 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=-0.89).
• BP6: Variant 10-104046552-C-A is Benign according to our data. Variant chr10-104046552-C-A is described in ClinVar as Benign. ClinVar VariationId is 1273533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL17A1	NM_000494.4	c.2362+195G>T		intron_variant	Intron 32 of 55	ENST00000648076.2	NP_000485.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL17A1	ENST00000648076.2	c.2362+195G>T		intron_variant	Intron 32 of 55		NM_000494.4	ENSP00000497653.1
COL17A1	ENST00000369733.8	c.2362+195G>T		intron_variant	Intron 31 of 50	5		ENSP00000358748.3

Frequencies

GnomAD3 genomes AF: 0.709 AC: 107761 AN: 151908 Hom.: 38397 Cov.: 31

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.724

Gnomad AMR AF: 0.777

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.696

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.709 AC: 107861 AN: 152028 Hom.: 38439 Cov.: 31 AF XY: 0.711 AC XY: 52873 AN XY: 74324

African (AFR) AF: 0.705 AC: 29250 AN: 41462

American (AMR) AF: 0.777 AC: 11879 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2327 AN: 3468

East Asian (EAS) AF: 0.666 AC: 3433 AN: 5154

South Asian (SAS) AF: 0.789 AC: 3804 AN: 4820

European-Finnish (FIN) AF: 0.653 AC: 6900 AN: 10564

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47947 AN: 67962

Other (OTH) AF: 0.695 AC: 1465 AN: 2108

Alfa AF: 0.709 Hom.: 82120

Bravo AF: 0.717

Asia WGS AF: 0.707 AC: 2455 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

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	-0.89
CADD	Benign	10
DANN	Benign	0.61
PhyloP100		1.3
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: rs805721; hg19: chr10-105806310; COSMIC: COSV62227220; COSMIC: COSV62227220;