NM_000494.4:c.2107A>G

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.2107A>G(p.Met703Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,613,354 control chromosomes in the GnomAD database, including 522,823 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 0.73 ( 41598 hom., cov: 31)

Exomes 𝑓: 0.81 ( 481225 hom. )

Consequence

COL17A1
NM_000494.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.188

Publications

47 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=7.5010075E-6).

BP6

Variant 10-104050642-T-C is Benign according to our data. Variant chr10-104050642-T-C is described in ClinVar as Benign. ClinVar VariationId is 256267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL17A1	NM_000494.4 link	c.2107A>G	p.Met703Val	missense_variant	Exon 27 of 56	ENST00000648076.2	NP_000485.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL17A1	ENST00000648076.2 link	c.2107A>G	p.Met703Val	missense_variant	Exon 27 of 56		NM_000494.4	ENSP00000497653.1
COL17A1	ENST00000369733.8 link	c.2107A>G	p.Met703Val	missense_variant	Exon 26 of 51	5		ENSP00000358748.3

Frequencies

GnomAD3 genomes

AF:

0.728

AC:

110640

AN:

151924

Hom.:

41602

Cov.:

show subpopulations

Gnomad AFR

AF:

0.522

Gnomad AMI

AF:

0.913

Gnomad AMR

AF:

0.799

Gnomad ASJ

AF:

0.814

Gnomad EAS

AF:

0.785

Gnomad SAS

AF:

0.741

Gnomad FIN

AF:

0.747

Gnomad MID

AF:

0.797

Gnomad NFE

AF:

0.821

Gnomad OTH

AF:

0.766

GnomAD2 exomes

AF:

0.785

AC:

197385

AN:

251486

AF XY:

0.787

show subpopulations

Gnomad AFR exome

AF:

0.520

Gnomad AMR exome

AF:

0.829

Gnomad ASJ exome

AF:

0.803

Gnomad EAS exome

AF:

0.789

Gnomad FIN exome

AF:

0.745

Gnomad NFE exome

AF:

0.822

Gnomad OTH exome

AF:

0.796

GnomAD4 exome

AF:

0.810

AC:

1182935

AN:

1461312

Hom.:

481225

Cov.:

100

AF XY:

0.809

AC XY:

587897

AN XY:

726988

show subpopulations

African (AFR)

AF:

0.507

AC:

16961

AN:

33472

American (AMR)

AF:

0.825

AC:

36881

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.806

AC:

21073

AN:

26136

East Asian (EAS)

AF:

0.780

AC:

30949

AN:

39700

South Asian (SAS)

AF:

0.762

AC:

65722

AN:

86222

European-Finnish (FIN)

AF:

0.751

AC:

40104

AN:

53418

Middle Eastern (MID)

AF:

0.800

AC:

4237

AN:

5298

European-Non Finnish (NFE)

AF:

0.827

AC:

919165

AN:

1111998

Other (OTH)

AF:

0.793

AC:

47843

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

16000

32001

48001

64002

80002

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20940

41880

62820

83760

104700

<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:

0.728

AC:

110662

AN:

152042

Hom.:

41598

Cov.:

AF XY:

0.727

AC XY:

53993

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.521

AC:

21586

AN:

41398

American (AMR)

AF:

0.799

AC:

12226

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.814

AC:

2823

AN:

3470

East Asian (EAS)

AF:

0.786

AC:

4059

AN:

5166

South Asian (SAS)

AF:

0.742

AC:

3571

AN:

4814

European-Finnish (FIN)

AF:

0.747

AC:

7913

AN:

10590

Middle Eastern (MID)

AF:

0.786

AC:

231

AN:

294

European-Non Finnish (NFE)

AF:

0.821

AC:

55817

AN:

67992

Other (OTH)

AF:

0.760

AC:

1603

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1429

2858

4287

5716

7145

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.789

Hom.:

143575

Bravo

AF:

0.724

TwinsUK

AF:

0.832

AC:

3084

ALSPAC

AF:

0.831

AC:

3204

ESP6500AA

AF:

0.525

AC:

2313

ESP6500EA

AF:

0.818

AC:

7039

ExAC

AF:

0.780

AC:

94732

Asia WGS

AF:

0.690

AC:

2400

AN:

3478

EpiCase

AF:

0.826

EpiControl

AF:

0.821

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

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. -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

4.8

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.20

.;T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.36

T;.;T

MetaRNN

Benign

0.0000075

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.080

N;N;N

PhyloP100

-0.19

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.93

N;N;.

REVEL

Benign

0.22

Sift

Benign

0.56

T;T;.

Sift4G

Benign

0.29

T;T;.

Polyphen

0.0

.;B;B

Vest4

0.077

MPC

0.067

ClinPred

0.0010

GERP RS

-4.2

Varity_R

0.049

gMVP

0.21

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over