chr3-48566281-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_000094.4(COL7A1):c.8393T>A(p.Met2798Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

COL7A1
NM_000094.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.25

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 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

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.899

PP5

Variant 3-48566281-A-T is Pathogenic according to our data. Variant chr3-48566281-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48566281-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL7A1	NM_000094.4 link	c.8393T>A	p.Met2798Lys	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.8393T>A	p.Met2798Lys	missense_variant	Exon 114 of 119		NM_000094.4	ENSP00000506558.1	Q02388-1
COL7A1	ENST00000328333.12 link	c.8393T>A	p.Met2798Lys	missense_variant	Exon 113 of 118	1		ENSP00000332371.8	Q02388-1
COL7A1	ENST00000487017.5 link	n.5032T>A		non_coding_transcript_exon_variant	Exon 78 of 83	5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Recessive dystrophic epidermolysis bullosa

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2024	Variant summary: COL7A1 c.8393T>A (p.Met2798Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 230376 control chromosomes. c.8393T>A has been reported in the literature in individuals affected with Dystrophic Epidermolysis Bullosa, Recessive (Christiano_1993). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 8513326). ClinVar contains an entry for this variant (Variation ID: 17423). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1993	- -

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

Apr 05, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 12, 2024

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 2798 of the COL7A1 protein (p.Met2798Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 8513326). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17423). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL7A1 protein function. This variant disrupts the p.Met2798 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 34435747). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.77

Sift

Benign

0.11

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.95

MutPred

0.73

Gain of ubiquitination at M2798 (P = 0.017);

MVP

0.91

MPC

0.86

ClinPred

0.97

GERP RS

5.1

Varity_R

0.49

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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