rs121912850

Variant names:

• chr3-48575116-C-T
• rs121912850
• NM_000094.4:c.6227G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000094.4(COL7A1):​c.6227G>A​(p.Gly2076Asp) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2076V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL7A1 NM_000094.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.06

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-48575116-C-A is described in Lovd as [Pathogenic].
• 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, 0.993
• PP5: Variant 3-48575116-C-T is Pathogenic according to our data. Variant chr3-48575116-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17457.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-48575116-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL7A1	NM_000094.4	c.6227G>A	p.Gly2076Asp	missense_variant	Exon 76 of 119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1	c.6227G>A	p.Gly2076Asp	missense_variant	Exon 76 of 119		NM_000094.4	ENSP00000506558.1
COL7A1	ENST00000328333.12	c.6227G>A	p.Gly2076Asp	missense_variant	Exon 75 of 118	1		ENSP00000332371.8
COL7A1	ENST00000487017.5	n.2144G>A		non_coding_transcript_exon_variant	Exon 41 of 83	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Generalized dominant dystrophic epidermolysis bullosa Pathogenic:2

Nov 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 14, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.8	H
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.96		Loss of glycosylation at P2081 (P = 0.0357);
MVP		0.98
MPC		0.32
ClinPred		0.97	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		1.0

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

Other links and lift over

dbSNP: rs121912850; hg19: chr3-48612549;