rs805708

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.27

Publications

41 publications found

Variant links:

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

COL17A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Selected	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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL17A1	ENST00000648076.2	MANE Select	c.629C>T	p.Thr210Met	missense	Exon 10 of 56	ENSP00000497653.1
COL17A1	ENST00000393211.3	TSL:1	c.629C>T	p.Thr210Met	missense	Exon 10 of 15	ENSP00000376905.3
COL17A1	ENST00000369733.8	TSL:5	c.629C>T	p.Thr210Met	missense	Exon 9 of 51	ENSP00000358748.3

Frequencies

GnomAD3 genomes

AF:

0.601

AC:

91272

AN:

151980

Hom.:

29361

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.695

AC XY:

504716

AN XY:

726584

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

17028

34056

51083

68111

85139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19750

39500

59250

79000

98750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.600

AC:

91284

AN:

152096

Hom.:

29359

Cov.:

AF XY:

0.602

AC XY:

44749

AN XY:

74366

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1682

3363

5045

6726

8408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

754

1508

2262

3016

3770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Junctional epidermolysis bullosa, non-Herlitz type

Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Epithelial recurrent erosion dystrophy

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0000059

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.8

PhyloP100

7.3

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.27

Sift

Benign

0.090

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.76

MPC

0.068

ClinPred

0.045

GERP RS

5.6

Varity_R

0.11

gMVP

0.20

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over