3-48575218-G-C

Variant names:

• chr3-48575218-G-C
• NM_000094.4:c.6205C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000094.4(COL7A1):​c.6205C>G​(p.Arg2069Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2069C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL7A1 NM_000094.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.86

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a compositionally_biased_region Basic and acidic residues (size 17) in uniprot entity CO7A1_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) in NM_000094.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-48575218-G-A is described in Lovd as [Likely_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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL7A1	NM_000094.4	c.6205C>G	p.Arg2069Gly	missense_variant	Exon 75 of 119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1	c.6205C>G	p.Arg2069Gly	missense_variant	Exon 75 of 119		NM_000094.4	ENSP00000506558.1
COL7A1	ENST00000328333.12	c.6205C>G	p.Arg2069Gly	missense_variant	Exon 74 of 118	1		ENSP00000332371.8
COL7A1	ENST00000487017.5	n.2122C>G		non_coding_transcript_exon_variant	Exon 40 of 83	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	26
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.038
Eigen_PC	Benign	0.010
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.044	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.50
Sift	Benign	0.13	T
Sift4G	Uncertain	0.047	D
Polyphen		0.76	P
Vest4		0.59
MutPred		0.42		Loss of glycosylation at K2066 (P = 0.0018);
MVP		0.85
MPC		0.32
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.37
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-48612651;