3-48584486-G-C

Variant names:

• chr3-48584486-G-C
• NM_000094.4:c.4118C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000094.4(COL7A1):​c.4118C>G​(p.Ser1373Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL7A1 NM_000094.4 missense, splice_region
• Scores: Splicing: ADA: 0.001878
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72

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 Uncertain_significance. Variant got 3 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL7A1	NM_000094.4	c.4118C>G	p.Ser1373Trp	missense_variant, splice_region_variant	Exon 36 of 119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1	c.4118C>G	p.Ser1373Trp	missense_variant, splice_region_variant	Exon 36 of 119		NM_000094.4	ENSP00000506558.1
COL7A1	ENST00000328333.12	c.4118C>G	p.Ser1373Trp	missense_variant, splice_region_variant	Exon 35 of 118	1		ENSP00000332371.8
COL7A1	ENST00000487017.5	n.35C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 83	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461788 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.0087
Eigen_PC	Benign	-0.069
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.045	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.29
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.42
MutPred		0.35		Loss of glycosylation at P1376 (P = 0.0255);
MVP		0.91
MPC		0.34
ClinPred		0.89	D
GERP RS		3.6
Varity_R		0.11
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.26
SpliceAI score (max)		0.0		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: chr3-48621919;