rs1057518706
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_000094.4(COL7A1):c.6900+4A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
COL7A1
NM_000094.4 splice_donor_region, intron
NM_000094.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9788
2
Clinical Significance
Conservation
PhyloP100: 1.46
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 3-48572667-T-C is Pathogenic according to our data. Variant chr3-48572667-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374314.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-48572667-T-C is described in Lovd as [Likely_pathogenic]. Variant chr3-48572667-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL7A1 | NM_000094.4 | c.6900+4A>G | splice_donor_region_variant, intron_variant | ENST00000681320.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.6900+4A>G | splice_donor_region_variant, intron_variant | NM_000094.4 | P1 | ||||
COL7A1 | ENST00000328333.12 | c.6900+4A>G | splice_donor_region_variant, intron_variant | 1 | P1 | ||||
COL7A1 | ENST00000487017.5 | n.2817+4A>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.89e-7 AC: 1AN: 1452080Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0AN XY: 721560
GnomAD4 exome
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1452080
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37
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0
AN XY:
721560
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2020 | Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16965329). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been observed in individual(s) with dystrophic epidermolysis bullosa (PMID: 10504458, 16965329, 17425959). ClinVar contains an entry for this variant (Variation ID: 374314). This sequence change falls in intron 87 of the COL7A1 gene. It does not directly change the encoded amino acid sequence of the COL7A1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). - |
Generalized dominant dystrophic epidermolysis bullosa Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | May 01, 2016 | Our laboratory has reported dual molecular diagnoses in COL7A1 (NM_000094.3:c.6900+4A>G) and DDX3X (NM_001356.3:c.1052G>A) in an individual with microcephaly, delayed motor milestones, delayed speech, hypotonia, hyperreflexia, repetitive behaviors, dysmorphic features, mild conductive hearing loss, mild epidermolysis bullosa (EB) and a history of prematurity and genital anomalies. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at