rs805708

Variant names:

• chr10-104064575-G-A
• rs805708
• NM_000494.4:c.629C>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.629C>T​(p.Thr210Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.687 in 1,612,832 control chromosomes in the GnomAD database, including 386,527 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. T210T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.60 (29359 hom., cov: 31)
  • Exomes 𝑓: 0.70 (357168 hom.)
• Consequence: COL17A1 NM_000494.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.27
• Publications: 42 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=5.8837804E-6).
• BP6: Variant 10-104064575-G-A is Benign according to our data. Variant chr10-104064575-G-A is described in ClinVar as Benign. ClinVar VariationId is 256276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.702 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.629C>T	p.Thr210Met	missense	Exon 10 of 56	NP_000485.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL17A1	ENST00000648076.2	MANE Select	c.629C>T	p.Thr210Met	missense	Exon 10 of 56	ENSP00000497653.1	Q9UMD9-1
	COL17A1	ENST00000393211.3	TSL:1	c.629C>T	p.Thr210Met	missense	Exon 10 of 15	ENSP00000376905.3	A2A2Y8
	COL17A1	ENST00000859462.1		c.629C>T	p.Thr210Met	missense	Exon 10 of 56	ENSP00000529521.1

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91272 AN: 151980 Hom.: 29361 Cov.: 31

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.673

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.622

GnomAD2 exomes AF: 0.676 AC: 168590 AN: 249226 AF XY: 0.677

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.770

Gnomad ASJ exome AF: 0.684

Gnomad EAS exome AF: 0.690

Gnomad FIN exome AF: 0.664

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.696 AC: 1016503 AN: 1460736 Hom.: 357168 Cov.: 48 AF XY: 0.695 AC XY: 504716 AN XY: 726584

African (AFR) AF: 0.330 AC: 11046 AN: 33468

American (AMR) AF: 0.760 AC: 33908 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 17976 AN: 26110

East Asian (EAS) AF: 0.708 AC: 28072 AN: 39664

South Asian (SAS) AF: 0.637 AC: 54887 AN: 86124

European-Finnish (FIN) AF: 0.666 AC: 35521 AN: 53356

Middle Eastern (MID) AF: 0.642 AC: 3699 AN: 5762

European-Non Finnish (NFE) AF: 0.712 AC: 790791 AN: 1111292

Other (OTH) AF: 0.673 AC: 40603 AN: 60358

GnomAD4 genome AF: 0.600 AC: 91284 AN: 152096 Hom.: 29359 Cov.: 31 AF XY: 0.602 AC XY: 44749 AN XY: 74366

African (AFR) AF: 0.342 AC: 14200 AN: 41480

American (AMR) AF: 0.698 AC: 10677 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 2418 AN: 3472

East Asian (EAS) AF: 0.689 AC: 3550 AN: 5152

South Asian (SAS) AF: 0.632 AC: 3050 AN: 4824

European-Finnish (FIN) AF: 0.673 AC: 7132 AN: 10590

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.707 AC: 48040 AN: 67964

Other (OTH) AF: 0.615 AC: 1297 AN: 2108

Alfa AF: 0.670 Hom.: 120682

Bravo AF: 0.593

TwinsUK AF: 0.712 AC: 2640

ALSPAC AF: 0.714 AC: 2753

ESP6500AA AF: 0.355 AC: 1564

ESP6500EA AF: 0.703 AC: 6046

ExAC AF: 0.666 AC: 80816

Asia WGS AF: 0.569 AC: 1980 AN: 3478

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	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0000059	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.3
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.27
Sift	Benign	0.090	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.76
MPC		0.068
ClinPred		0.045	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.20
Mutation Taster		=98/2	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: rs805708; hg19: chr10-105824333; COSMIC: COSV107437985; COSMIC: COSV107437985;