rs2228561

Variant names:

Variant summary

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

The NM_000094.4(COL7A1):c.1784C>T(p.Pro595Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,613,976 control chromosomes in the GnomAD database, including 15,198 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P595P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.10 ( 972 hom., cov: 32)

Exomes 𝑓: 0.13 ( 14226 hom. )

Consequence

COL7A1
NM_000094.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.742

Publications

54 publications found

Variant links:

Genes affected

COL7A1 (HGNC:2214): (collagen type VII alpha 1 chain) This gene encodes the alpha chain of type VII collagen. The type VII collagen fibril, composed of three identical alpha collagen chains, is restricted to the basement zone beneath stratified squamous epithelia. It functions as an anchoring fibril between the external epithelia and the underlying stroma. Mutations in this gene are associated with all forms of dystrophic epidermolysis bullosa. In the absence of mutations, however, an acquired form of this disease can result from an autoimmune response made to type VII collagen. [provided by RefSeq, Jul 2008]

COL7A1 Gene-Disease associations (from GenCC):

epidermolysis bullosa with congenital localized absence of skin and deformity of nails
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
dystrophic epidermolysis bullosa pruriginosa
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
recessive dystrophic epidermolysis bullosa
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp, Ambry Genetics, G2P, ClinGen
generalized dominant dystrophic epidermolysis bullosa
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
pretibial dystrophic epidermolysis bullosa
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
transient bullous dermolysis of the newborn
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
acral dystrophic epidermolysis bullosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dystrophic epidermolysis bullosa, nails only
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
recessive dystrophic epidermolysis bullosa inversa
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
recessive dystrophic epidermolysis bullosa-generalized other
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

COL7A1 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=0.002085656).

BP6

Variant 3-48590581-G-A is Benign according to our data. Variant chr3-48590581-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL7A1	NM_000094.4 link	c.1784C>T	p.Pro595Leu	missense_variant	Exon 15 of 119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1 link	c.1784C>T	p.Pro595Leu	missense_variant	Exon 15 of 119		NM_000094.4	ENSP00000506558.1
COL7A1	ENST00000328333.12 link	c.1784C>T	p.Pro595Leu	missense_variant	Exon 14 of 118	1		ENSP00000332371.8

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15590

AN:

152040

Hom.:

971

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0514

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.0695

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.0320

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.136

Gnomad OTH

AF:

0.0892

GnomAD2 exomes

AF:

0.117

AC:

29334

AN:

251310

AF XY:

0.124

show subpopulations

Gnomad AFR exome

AF:

0.0466

Gnomad AMR exome

AF:

0.0714

Gnomad ASJ exome

AF:

0.0971

Gnomad EAS exome

AF:

0.0256

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.131

Gnomad OTH exome

AF:

0.118

GnomAD4 exome

AF:

0.134

AC:

195720

AN:

1461818

Hom.:

14226

Cov.:

AF XY:

0.136

AC XY:

99030

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0459

AC:

1538

AN:

33480

American (AMR)

AF:

0.0726

AC:

3247

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

2648

AN:

26136

East Asian (EAS)

AF:

0.0199

AC:

789

AN:

39700

South Asian (SAS)

AF:

0.216

AC:

18601

AN:

86258

European-Finnish (FIN)

AF:

0.114

AC:

6059

AN:

53368

Middle Eastern (MID)

AF:

0.0517

AC:

298

AN:

5768

European-Non Finnish (NFE)

AF:

0.139

AC:

155100

AN:

1111996

Other (OTH)

AF:

0.123

AC:

7440

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

13078

26155

39233

52310

65388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5590

11180

16770

22360

27950

<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:

0.102

AC:

15591

AN:

152158

Hom.:

972

Cov.:

AF XY:

0.103

AC XY:

7664

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0514

AC:

2135

AN:

41506

American (AMR)

AF:

0.0693

AC:

1059

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

365

AN:

3466

East Asian (EAS)

AF:

0.0313

AC:

162

AN:

5178

South Asian (SAS)

AF:

0.225

AC:

1086

AN:

4826

European-Finnish (FIN)

AF:

0.108

AC:

1146

AN:

10596

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.136

AC:

9224

AN:

67994

Other (OTH)

AF:

0.0882

AC:

186

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

718

1437

2155

2874

3592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

194

388

582

776

970

<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:

0.119

Hom.:

5337

Bravo

AF:

0.0927

TwinsUK

AF:

0.139

AC:

514

ALSPAC

AF:

0.143

AC:

553

ESP6500AA

AF:

0.0538

AC:

237

ESP6500EA

AF:

0.127

AC:

1093

ExAC

AF:

0.119

AC:

14462

Asia WGS

AF:

0.117

AC:

409

AN:

3478

EpiCase

AF:

0.123

EpiControl

AF:

0.121

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 27, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Epidermolysis bullosa dystrophica

Benign:2

Jan 13, 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.

Nov 21, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Recessive dystrophic epidermolysis bullosa

Benign:1

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone, for Epidermolysis bullosa dystrophica, autosomal recessive; rdeb, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

3.9

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.18

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-0.74

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.49

REVEL

Benign

0.10

Sift

Benign

0.41

Sift4G

Benign

0.83

Vest4

0.042

ClinPred

0.000025

GERP RS

-3.0

Varity_R

0.020

gMVP

0.24

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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