rs17116350

Variant names:

• chr10-104033992-T-C
• rs17116350
• NM_000494.4:c.4109A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-104033992-T-C
• chr10-104033992-T-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.4109A>G​(p.Asp1370Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,936 control chromosomes in the GnomAD database, including 50,100 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 (★★). Synonymous variant affecting the same amino acid position (i.e. D1370D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (6098 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44002 hom.)
• Consequence: COL17A1 NM_000494.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.157
• Publications: 27 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=0.0024353564).
• BP6: Variant 10-104033992-T-C is Benign according to our data. Variant chr10-104033992-T-C is described in ClinVar as Benign. ClinVar VariationId is 256275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 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.4109A>G	p.Asp1370Gly	missense	Exon 52 of 56	NP_000485.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL17A1	ENST00000648076.2	MANE Select	c.4109A>G	p.Asp1370Gly	missense	Exon 52 of 56	ENSP00000497653.1	Q9UMD9-1
	COL17A1	ENST00000859462.1		c.4109A>G	p.Asp1370Gly	missense	Exon 52 of 56	ENSP00000529521.1
	COL17A1	ENST00000859464.1		c.4106A>G	p.Asp1369Gly	missense	Exon 52 of 56	ENSP00000529523.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42141 AN: 151950 Hom.: 6090 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.258

GnomAD2 exomes AF: 0.244 AC: 61207 AN: 251344 AF XY: 0.243

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.244 AC: 356318 AN: 1461866 Hom.: 44002 Cov.: 39 AF XY: 0.243 AC XY: 176755 AN XY: 727238

African (AFR) AF: 0.373 AC: 12473 AN: 33478

American (AMR) AF: 0.230 AC: 10276 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 6646 AN: 26136

East Asian (EAS) AF: 0.142 AC: 5649 AN: 39700

South Asian (SAS) AF: 0.235 AC: 20305 AN: 86258

European-Finnish (FIN) AF: 0.249 AC: 13310 AN: 53402

Middle Eastern (MID) AF: 0.264 AC: 1525 AN: 5768

European-Non Finnish (NFE) AF: 0.244 AC: 271327 AN: 1112004

Other (OTH) AF: 0.245 AC: 14807 AN: 60396

GnomAD4 genome AF: 0.277 AC: 42171 AN: 152070 Hom.: 6098 Cov.: 32 AF XY: 0.275 AC XY: 20441 AN XY: 74330

African (AFR) AF: 0.375 AC: 15530 AN: 41464

American (AMR) AF: 0.250 AC: 3829 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 877 AN: 3468

East Asian (EAS) AF: 0.142 AC: 735 AN: 5170

South Asian (SAS) AF: 0.240 AC: 1154 AN: 4810

European-Finnish (FIN) AF: 0.241 AC: 2553 AN: 10584

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16693 AN: 67960

Other (OTH) AF: 0.258 AC: 545 AN: 2114

Alfa AF: 0.251 Hom.: 12326

Bravo AF: 0.281

TwinsUK AF: 0.249 AC: 925

ALSPAC AF: 0.261 AC: 1005

ESP6500AA AF: 0.374 AC: 1649

ESP6500EA AF: 0.247 AC: 2126

ExAC AF: 0.248 AC: 30111

Asia WGS AF: 0.193 AC: 671 AN: 3478

EpiCase AF: 0.255

EpiControl AF: 0.253

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	0.068
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.67
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.015	N
PhyloP100		0.16
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.18
Sift	Benign	0.54	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.085
ClinPred		0.00040	T
GERP RS		-0.37
Varity_R		0.046
gMVP		0.31
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs17116350; hg19: chr10-105793750; COSMIC: COSV59823759; COSMIC: COSV59823759;