rs864321654

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong

The NM_000094.4(COL7A1):​c.5000G>A​(p.Gly1667Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G1667G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

COL7A1
NM_000094.4 missense

Scores

16
2
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.72
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000094.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL7A1. . Gene score misZ 1.5899 (greater than the threshold 3.09). Trascript score misZ 4.0428 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.992

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL7A1NM_000094.4 linkuse as main transcriptc.5000G>A p.Gly1667Glu missense_variant 55/119 ENST00000681320.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL7A1ENST00000681320.1 linkuse as main transcriptc.5000G>A p.Gly1667Glu missense_variant 55/119 NM_000094.4 P1Q02388-1
COL7A1ENST00000328333.12 linkuse as main transcriptc.5000G>A p.Gly1667Glu missense_variant 54/1181 P1Q02388-1
COL7A1ENST00000487017.5 linkuse as main transcriptn.917G>A non_coding_transcript_exon_variant 20/835

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Recessive dystrophic epidermolysis bullosa Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingStrand Center for Genomics and Personalized Medicine, Strand Life Sciences Pvt Ltd-The identified novel heterozygous missense substitution (p.Gly1667Glu) alters a conserved residue in the protein. The identified variant lies in the triple helical domain of the protein (1254-2784 aa). Another missense variant, p.Pro1699Leu which lies in the vicinity of the identified variant, and also lies in the triple helical domain, has been reported as 'pathogenic' in the ClinVar database (SCV000034653) with respect to epidermolysis bullosa, pretibial, autosomal recessive. Additionally, variations that typically involve glycine substitutions within the type VII collagen triple helix have been associated with a spectrum of dystrophic epidermolysis bullosa phenotypes [PMID:8644729]. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
30
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.80
D
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.62
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.9
H
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.80
D
PROVEAN
Pathogenic
-4.8
D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.94
Loss of glycosylation at K1672 (P = 0.0123);
MVP
0.99
MPC
0.32
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.75
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.19
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.

Other links and lift over

dbSNP: rs864321654; hg19: chr3-48618066; API