rs2476958

Positions:

• chr10-104037061-A-C
• chr10-104037061-A-G
• chr10-104037061-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000494.4(COL17A1):​c.3261T>G​(p.Ile1087Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I1087I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL17A1 NM_000494.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36269462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL17A1	NM_000494.4	c.3261T>G	p.Ile1087Met	missense_variant	47/56	ENST00000648076.2	NP_000485.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL17A1	ENST00000648076.2	c.3261T>G	p.Ile1087Met	missense_variant	47/56		NM_000494.4	ENSP00000497653	A2
COL17A1	ENST00000369733.8	c.3126T>G	p.Ile1042Met	missense_variant	43/51	5		ENSP00000358748	P4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.87e-7 AC: 1 AN: 1454726 Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0 AN XY: 722768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.34	.;T;T
Eigen	Benign	0.0028
Eigen_PC	Benign	-0.0081
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.75	T;.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.7	.;L;L
MutationTaster	Benign	0.85	N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Uncertain	0.56
Sift	Benign	0.032	D;T;.
Sift4G	Uncertain	0.040	D;T;.
Polyphen		0.99	.;D;D
Vest4		0.49
MutPred		0.44		.;Gain of disorder (P = 0.0301);Gain of disorder (P = 0.0301);
MVP		0.75
MPC		0.41
ClinPred		0.74	D
GERP RS		3.7
Varity_R		0.088
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs2476958; hg19: chr10-105796819;