chr3-48586983-G-A

Position:

• chr3-48586983-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000094.4(COL7A1):​c.3265C>T​(p.Gln1089*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL7A1 NM_000094.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.25

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-48586983-G-A is Pathogenic according to our data. Variant chr3-48586983-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL7A1	NM_000094.4	c.3265C>T	p.Gln1089*	stop_gained	25/119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1	c.3265C>T	p.Gln1089*	stop_gained	25/119		NM_000094.4	ENSP00000506558.1
COL7A1	ENST00000328333.12	c.3265C>T	p.Gln1089*	stop_gained	24/118	1		ENSP00000332371.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Recessive dystrophic epidermolysis bullosa Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	The observed stop gain c.3265C>T(p.Gln1089Ter) variant in COL7A1 gene variant has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.3265C>T variant is absent in gnomAD Exomes database. This variant has been reported to the ClinVar database as Likely pathogenic. Computational evidence (MutationTaster - Disease causing) predict damaging effect on protein structure and function for this variant. The nucleotide change c.3265C>T in COL7A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 30, 2017	The NM_000094.3(COL7A1):c.3265C>T heterozygous nonsense variant was identified in exon 24 of COL7A1. This nonsense variant introduces a stop codon at amino acid position 1089, NP_000085.1(COL7A1):p.(Gln1089*). This variant is predicted to result in loss of protein function either through truncation (>50% of the protein, including multiple triple helix repeats) or nonsense-mediated decay. This variant is not present in the gnomAD population database and has not been previously observed in other clinical cases. However, other truncating variants downstream of c.3265C>T in COL7A1 have been reported as pathogenic in individuals with dystrophic epidermolysis bullosa (ClinVar). Based on current information and in association with the NM_000094.3(COL7A1):c.1732C>T nonsense variant, this variant has been classified as LIKELY PATHOGENIC. The presence of these two nonsense variants suggests a possible compound heterozygous mode of inheritance which is consistent with dystrophic epidermolysis bullosa. -

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

Mar 13, 2024

- -

Epidermolysis bullosa Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Jul 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.88	D
Vest4		0.93
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1553612617; hg19: chr3-48624416;