rs797045142

Variant names:

• chr10-104039613-G-A
• rs797045142
• NM_000494.4:c.2816C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-104039613-G-A
• chr10-104039613-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_000494.4(COL17A1):​c.2816C>T​(p.Thr939Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL17A1 NM_000494.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.203
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-104039613-G-A is Pathogenic according to our data. Variant chr10-104039613-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208977.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10795075). . Strength limited to SUPPORTING due to the PP5.

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.2816C>T	p.Thr939Ile	missense	Exon 42 of 56	NP_000485.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL17A1	ENST00000648076.2	MANE Select	c.2816C>T	p.Thr939Ile	missense	Exon 42 of 56	ENSP00000497653.1
	COL17A1	ENST00000369733.8	TSL:5	c.2762-492C>T		intron	N/A	ENSP00000358748.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Epithelial recurrent erosion dystrophy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.27	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.030	N
PhyloP100		0.20
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.66	N
REVEL	Pathogenic	0.70
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.46		Loss of phosphorylation at T939 (P = 0.0312)
MVP		0.28
MPC		0.22
ClinPred		0.13	T
GERP RS		-3.5
Varity_R		0.038
gMVP		0.18
Mutation Taster		=30/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs797045142; hg19: chr10-105799371;