rs142566193

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2

The NM_000094.4(COL7A1):c.8371C>T(p.Arg2791Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00157 in 1,604,438 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

COL7A1
NM_000094.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:2

Conservation

PhyloP100: 5.24

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a region_of_interest Nonhelical region (NC2) (size 159) in uniprot entity CO7A1_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_000094.4

PP2

Missense variant in the COL7A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 223 curated pathogenic missense variants (we use a threshold of 10). The gene has 262 curated benign missense variants. Gene score misZ: 1.5899 (below the threshold of 3.09). Trascript score misZ: 4.0428 (above the threshold of 3.09). GenCC associations: The gene is linked to recessive dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa pruriginosa, recessive dystrophic epidermolysis bullosa-generalized other, transient bullous dermolysis of the newborn, epidermolysis bullosa with congenital localized absence of skin and deformity of nails, generalized dominant dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa, nails only, acral dystrophic epidermolysis bullosa, recessive dystrophic epidermolysis bullosa inversa, pretibial dystrophic epidermolysis bullosa.

BP4

Computational evidence support a benign effect (MetaRNN=0.26036757).

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL7A1	NM_000094.4 link	c.8371C>T	p.Arg2791Trp	missense_variant	Exon 114 of 119	ENST00000681320.1	NP_000085.1	Q02388-1Q59F16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL7A1	ENST00000681320.1 link	c.8371C>T	p.Arg2791Trp	missense_variant	Exon 114 of 119		NM_000094.4	ENSP00000506558.1	Q02388-1
COL7A1	ENST00000328333.12 link	c.8371C>T	p.Arg2791Trp	missense_variant	Exon 113 of 118	1		ENSP00000332371.8	Q02388-1
COL7A1	ENST00000487017.5 link	n.5010C>T		non_coding_transcript_exon_variant	Exon 78 of 83	5
COL7A1	ENST00000474432.1 link	n.*237C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

161

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00188

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00110

AC:

254

AN:

231330

Hom.:

AF XY:

0.00109

AC XY:

136

AN XY:

124510

show subpopulations

Gnomad AFR exome

AF:

0.000551

Gnomad AMR exome

AF:

0.000501

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000388

Gnomad FIN exome

AF:

0.000920

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00106

GnomAD4 exome

AF:

0.00162

AC:

2350

AN:

1452166

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1119

AN XY:

721322

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.000398

Gnomad4 ASJ exome

AF:

0.0000778

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000450

Gnomad4 FIN exome

AF:

0.000778

Gnomad4 NFE exome

AF:

0.00191

Gnomad4 OTH exome

AF:

0.00208

GnomAD4 genome

AF:

0.00106

AC:

161

AN:

152272

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00188

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00134

Hom.:

Bravo

AF:

0.00122

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00126

AC:

153

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Recessive dystrophic epidermolysis bullosa

Pathogenic:2

Oct 13, 2014

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

HUSP Clinical Genetics Laboratory, Hospital Universitario San Pedro De Logroño (HUSP)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL7A1 p.Arg2791Trp variant was identified in the literature as a compound heterozygous variant in 1 of 14 patients with dystrophic epidermolysis bullosa (Dang_2007_PMID:17425959). The variant was also identified as a compound heterozygous variant in a 62 year old man with dystrophic epidermolysis bullosa who also carried a p.Gly1281Valfs*44 variant (Mahto_2013_PMID:23786535). The variant was identified in dbSNP (ID: rs142566193), ClinVar (classified as likely pathogenic by Knight Diagnostic Laboratories,Oregon Health and Sciences University, and as uncertain significance by Ambry Genetics) and LOVD 3.0 (classified as pathogenic, likely pathogenic and VUS). The variant was identified in control databases in 284 of 262690 chromosomes (2 homozygous) at a frequency of 0.001081 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 213 of 120204 chromosomes (freq: 0.001772), Other in 8 of 6758 chromosomes (freq: 0.001184), European (Finnish) in 22 of 23032 chromosomes (freq: 0.000955), African in 14 of 23204 chromosomes (freq: 0.000603), Latino in 16 of 32778 chromosomes (freq: 0.000488) and South Asian in 11 of 28376 chromosomes (freq: 0.000388), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Arg2791 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Epidermolysis bullosa dystrophica

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Inborn genetic diseases

Uncertain:1

Sep 01, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epidermolysis bullosa dystrophica inversa, autosomal recessive

Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

COL7A1-related disorder

Benign:1

May 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Uncertain

0.70

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.26

MetaSVM

Uncertain

0.36

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.6

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.89

MVP

0.95

MPC

0.92

ClinPred

0.063

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over