rs786204774
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePM2PP3_ModeratePP5_Very_Strong
The NM_000094.4(COL7A1):c.7557+1G>T variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000094.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL7A1 | NM_000094.4 | c.7557+1G>T | splice_donor_variant | ENST00000681320.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.7557+1G>T | splice_donor_variant | NM_000094.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461874Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727234
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Epidermolysis bullosa dystrophica Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 07, 2013 | The 7557+1G>T variant in COL7A1 has not been reported in the literature or in large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the COL7A1 gene is an established disease mechanism in Epidermolysis bullosa dystrophica patients. It should be noted that mutations in COL7A1 gene have been associated with both autosomal recessive and dominant forms of this disease and the inheritance of each variant can only be determined based on its segregation pattern in families and molecular studies; however splicing mutations have been more frequently observed in autosomal recessive Epidermolysis bullosa dystrophica (Varki 2007). If this variant were to cause skipping of exon 100, it would cause a deletion of 12 amino acids between positions 2508-2519 and would not alter the protein reading-frame. It is currently unclear how this deletion would impact the protein, though two pathogenic missense variants have previously been reported in exon 100 (Almaani 2011), suggesting that this exon is likely to have an important role in protein function. In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 04, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This sequence change affects a donor splice site in intron 100 of the COL7A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL7A1 are known to be pathogenic (PMID: 16971478). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL7A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 189226). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at