rs35761247

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.3830C>T(p.Pro1277Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0518 in 1,613,924 control chromosomes in the GnomAD database, including 2,524 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1277P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.039 ( 157 hom., cov: 32)

Exomes 𝑓: 0.053 ( 2367 hom. )

Consequence

COL7A1
NM_000094.4 missense, splice_region

Scores

Splicing: ADA: 0.07784

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.53

Publications

22 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=0.012060225).

BP6

Variant 3-48585691-G-A is Benign according to our data. Variant chr3-48585691-G-A is described in ClinVar as Benign. ClinVar VariationId is 255109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL7A1	NM_000094.4 link	c.3830C>T	p.Pro1277Leu	missense_variant, splice_region_variant	Exon 31 of 119	ENST00000681320.1	NP_000085.1	Q02388-1Q59F16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1 link	c.3830C>T	p.Pro1277Leu	missense_variant, splice_region_variant	Exon 31 of 119		NM_000094.4	ENSP00000506558.1		Q02388-1
COL7A1	ENST00000328333.12 link	c.3830C>T	p.Pro1277Leu	missense_variant, splice_region_variant	Exon 30 of 118	1		ENSP00000332371.8		Q02388-1

Frequencies

GnomAD3 genomes

AF:

0.0394

AC:

5999

AN:

152092

Hom.:

156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00961

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0321

Gnomad ASJ

AF:

0.0380

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.0487

Gnomad FIN

AF:

0.0868

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0552

Gnomad OTH

AF:

0.0248

GnomAD2 exomes

AF:

0.0431

AC:

10825

AN:

251336

AF XY:

0.0455

show subpopulations

Gnomad AFR exome

AF:

0.00880

Gnomad AMR exome

AF:

0.0269

Gnomad ASJ exome

AF:

0.0331

Gnomad EAS exome

AF:

0.000979

Gnomad FIN exome

AF:

0.0857

Gnomad NFE exome

AF:

0.0493

Gnomad OTH exome

AF:

0.0440

GnomAD4 exome

AF:

0.0531

AC:

77627

AN:

1461714

Hom.:

2367

Cov.:

AF XY:

0.0531

AC XY:

38636

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.00774

AC:

259

AN:

33480

American (AMR)

AF:

0.0261

AC:

1166

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0335

AC:

876

AN:

26136

East Asian (EAS)

AF:

0.000957

AC:

AN:

39700

South Asian (SAS)

AF:

0.0570

AC:

4915

AN:

86258

European-Finnish (FIN)

AF:

0.0825

AC:

4394

AN:

53290

Middle Eastern (MID)

AF:

0.0262

AC:

151

AN:

5768

European-Non Finnish (NFE)

AF:

0.0564

AC:

62729

AN:

1111972

Other (OTH)

AF:

0.0513

AC:

3099

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

5093

10186

15278

20371

25464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2378

4756

7134

9512

11890

<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:

0.0394

AC:

5997

AN:

152210

Hom.:

157

Cov.:

AF XY:

0.0401

AC XY:

2985

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00963

AC:

400

AN:

41544

American (AMR)

AF:

0.0320

AC:

490

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0380

AC:

132

AN:

3472

East Asian (EAS)

AF:

0.00233

AC:

AN:

5160

South Asian (SAS)

AF:

0.0483

AC:

233

AN:

4826

European-Finnish (FIN)

AF:

0.0868

AC:

921

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0552

AC:

3750

AN:

67974

Other (OTH)

AF:

0.0246

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

311

622

933

1244

1555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0471

Hom.:

284

Bravo

AF:

0.0319

TwinsUK

AF:

0.0572

AC:

212

ALSPAC

AF:

0.0558

AC:

215

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.0555

AC:

477

ExAC

AF:

0.0418

AC:

5076

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0495

EpiControl

AF:

0.0474

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epidermolysis bullosa dystrophica

Benign:2

Nov 22, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

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, 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

0.10

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.67

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.5

PhyloP100

4.5

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.62

Sift

Uncertain

0.014

Sift4G

Benign

0.067

Polyphen

1.0

Vest4

0.22

MPC

0.25

ClinPred

0.024

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.81

Mutation Taster

=64/36

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.078

dbscSNV1_RF

Benign

0.24

SpliceAI score (max)

0.010

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