rs200972872

Positions:

chr3-48576249-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The NM_000094.4(COL7A1):c.5820G>A(p.Pro1940=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

COL7A1
NM_000094.4 splice_region, synonymous

Scores

Splicing: ADA: 0.9996

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: -0.234

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_pathogenic. Variant got 9 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 3-48576249-C-T is Pathogenic according to our data. Variant chr3-48576249-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48576249-C-T is described in Lovd as [Pathogenic]. Variant chr3-48576249-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL7A1	NM_000094.4 linkuse as main transcript	c.5820G>A	p.Pro1940=	splice_region_variant, synonymous_variant	71/119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1 linkuse as main transcript	c.5820G>A	p.Pro1940=	splice_region_variant, synonymous_variant	71/119		NM_000094.4	ENSP00000506558	P1	Q02388-1
COL7A1	ENST00000328333.12 linkuse as main transcript	c.5820G>A	p.Pro1940=	splice_region_variant, synonymous_variant	70/118	1		ENSP00000332371	P1	Q02388-1
COL7A1	ENST00000487017.5 linkuse as main transcript	n.1737G>A		splice_region_variant, non_coding_transcript_exon_variant	36/83	5

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000877

AC:

AN:

250822

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000114

AC:

166

AN:

1461382

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000127

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000183

Hom.:

Bravo

AF:

0.000128

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000415

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2023	RNA studies demonstrate that the variant reduces the quality of the splice donor site in intron 70, causing abnormal gene splicing and exon skipping of exon 70, in approximately 40% of transcripts (PMID: 9804332); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 33969388, 9804332, 21448560, 12485454, 31589614, 34426522, 31001817, 31930626, 33274474) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change affects codon 1940 of the COL7A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL7A1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs200972872, gnomAD 0.02%). This variant has been observed in individuals with autosomal recessive dystrophic epidermolysis bullosa (PMID: 9804332, 31001817, 31930626). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 431810). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 70, but is expected to preserve the integrity of the reading-frame (PMID: 9804332). This variant disrupts the triple helix domain of COL7A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236), and variants at these glycine residues in COL7A1 are more frequently observed in individuals with disease than in the general population (PMID: 22058051). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. For these reasons, this variant has been classified as Pathogenic. -

COL7A1-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 24, 2024	The COL7A1 c.5820G>A variant is not predicted to result in an amino acid change (p.=). This variant leads to skipping of exon 70 of the COL7A1 gene (Terracina et al. 1998. PubMed ID: 9804332). This variant has been reported in the compound heterozygous state in an individual with a mild form of dystrophic epidermolysis bullosa (Terracina et al. 1998. PubMed ID: 9804332; Supplementary Table SII, Almaani et al. 2011. PubMed ID: 21448560; Mariath et al. 2019. PubMed ID: 31001817). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2023	Variant summary: COL7A1 c.5820G>A (p.Pro1940Pro) results in a synonymous change to the encoded protein sequence and also alters the last nucleotide of Exon 71 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site, and two predict the variant weakens the same 5' donor site. At least two publications report experimental evidence that this variant affects mRNA splicing, leading to both exon skipping and intron retention (e.g., Terracina_1998, Vahidnezhad_2020). The variant allele was found at a frequency of 8.8e-05 in 250822 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5820G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Dystrophic Epidermolysis Bullosa, Recessive (e.g., Terracina_1998, Gardella_2002, Vahidnezhad_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating the impact of the variant, finding markedly reduced COL7A1 transcript levels in a whole-skin biopsy from a homozgyous patient (e.g., Vahidnezhad_2020). The following publications have been ascertained in the context of this evaluation (PMID: 12485454, 9804332, 31930626). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (pathogenic, n = 5; likely pathogenic, n = 1; VUS, n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Recessive dystrophic epidermolysis bullosa;C0268371:Dominant dystrophic epidermolysis bullosa with absence of skin;C0432321:Pretibial dystrophic epidermolysis bullosa;C0432322:Generalized dominant dystrophic epidermolysis bullosa;C1275114:Epidermolysis bullosa pruriginosa;C1843761:Nonsyndromic congenital nail disorder 8;C1851573:Transient bullous dermolysis of the newborn

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Epidermolysis bullosa dystrophica

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Biomedical Innovation Departament, CIEMAT

Nov 26, 2018

- -

Recessive dystrophic epidermolysis bullosa

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires

Mar 14, 2022

- -

Epidermolysis bullosa dystrophica inversa, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Epidermolysis bullosa dystrophica, autosomal recessive, localisata variant

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.23

Position offset: 0

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