rs805698

Variant names:

• chr10-104057158-C-T
• rs805698
• NM_000494.4:c.1282G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-104057158-C-T
• chr10-104057158-C-G

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.1282G>A​(p.Gly428Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.963 in 1,613,840 control chromosomes in the GnomAD database, including 755,323 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (58588 hom., cov: 32)
  • Exomes 𝑓: 0.97 (696735 hom.)
• Consequence: COL17A1 NM_000494.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.699
• Publications: 38 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epidermolysis bullosa, junctional 4, intermediate

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, G2P
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, 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 (MetaRNN=8.6531384E-7).
• BP6: Variant 10-104057158-C-T is Benign according to our data. Variant chr10-104057158-C-T is described in ClinVar as Benign. ClinVar VariationId is 256266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.988 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL17A1	NM_000494.4	MANE Select	c.1282G>A	p.Gly428Ser	missense	Exon 17 of 56	NP_000485.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL17A1	ENST00000648076.2	MANE Select	c.1282G>A	p.Gly428Ser	missense	Exon 17 of 56	ENSP00000497653.1	Q9UMD9-1
	COL17A1	ENST00000859462.1		c.1282G>A	p.Gly428Ser	missense	Exon 17 of 56	ENSP00000529521.1
	COL17A1	ENST00000859464.1		c.1279G>A	p.Gly427Ser	missense	Exon 17 of 56	ENSP00000529523.1

Frequencies

GnomAD3 genomes AF: 0.857 AC: 130310 AN: 151994 Hom.: 58581 Cov.: 32

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.927

Gnomad ASJ AF: 0.986

Gnomad EAS AF: 0.884

Gnomad SAS AF: 0.943

Gnomad FIN AF: 0.944

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.994

Gnomad OTH AF: 0.900

GnomAD2 exomes AF: 0.940 AC: 233587 AN: 248608 AF XY: 0.948

Gnomad AFR exome AF: 0.551

Gnomad AMR exome AF: 0.947

Gnomad ASJ exome AF: 0.987

Gnomad EAS exome AF: 0.888

Gnomad FIN exome AF: 0.944

Gnomad NFE exome AF: 0.994

Gnomad OTH exome AF: 0.956

GnomAD4 exome AF: 0.974 AC: 1423027 AN: 1461728 Hom.: 696735 Cov.: 59 AF XY: 0.975 AC XY: 708647 AN XY: 727168

African (AFR) AF: 0.535 AC: 17903 AN: 33468

American (AMR) AF: 0.945 AC: 42278 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.985 AC: 25746 AN: 26128

East Asian (EAS) AF: 0.866 AC: 34382 AN: 39694

South Asian (SAS) AF: 0.950 AC: 81940 AN: 86256

European-Finnish (FIN) AF: 0.946 AC: 50524 AN: 53416

Middle Eastern (MID) AF: 0.955 AC: 5498 AN: 5758

European-Non Finnish (NFE) AF: 0.996 AC: 1107643 AN: 1111904

Other (OTH) AF: 0.946 AC: 57113 AN: 60380

GnomAD4 genome AF: 0.857 AC: 130352 AN: 152112 Hom.: 58588 Cov.: 32 AF XY: 0.859 AC XY: 63857 AN XY: 74368

African (AFR) AF: 0.554 AC: 22932 AN: 41426

American (AMR) AF: 0.927 AC: 14181 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.986 AC: 3422 AN: 3472

East Asian (EAS) AF: 0.884 AC: 4549 AN: 5144

South Asian (SAS) AF: 0.944 AC: 4554 AN: 4824

European-Finnish (FIN) AF: 0.944 AC: 10019 AN: 10608

Middle Eastern (MID) AF: 0.929 AC: 273 AN: 294

European-Non Finnish (NFE) AF: 0.994 AC: 67610 AN: 68020

Other (OTH) AF: 0.901 AC: 1902 AN: 2112

Alfa AF: 0.945 Hom.: 196028

Bravo AF: 0.839

TwinsUK AF: 0.994 AC: 3687

ALSPAC AF: 0.996 AC: 3838

ESP6500AA AF: 0.567 AC: 2498

ESP6500EA AF: 0.993 AC: 8539

ExAC AF: 0.934 AC: 113433

EpiCase AF: 0.994

EpiControl AF: 0.993

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.1
DANN	Benign	0.72
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	8.7e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.70
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.23
Sift	Benign	0.48	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.065
MPC		0.066
ClinPred		0.0089	T
GERP RS		1.7
Varity_R		0.019
gMVP		0.20
Mutation Taster		=98/2	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: rs805698; hg19: chr10-105816916; COSMIC: COSV62226343; COSMIC: COSV62226343;