chr9-134780147-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000093.5(COL5A1):c.2430+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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_000093.5 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.2430+1G>A | splice_donor_variant, intron_variant | Intron 28 of 65 | ENST00000371817.8 | NP_000084.3 | ||
COL5A1 | NM_001278074.1 | c.2430+1G>A | splice_donor_variant, intron_variant | Intron 28 of 65 | NP_001265003.1 | |||
COL5A1 | XM_017014266.3 | c.2430+1G>A | splice_donor_variant, intron_variant | Intron 28 of 64 | XP_016869755.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.2430+1G>A | splice_donor_variant, intron_variant | Intron 28 of 65 | 1 | NM_000093.5 | ENSP00000360882.3 | |||
COL5A1 | ENST00000371820.4 | c.2430+1G>A | splice_donor_variant, intron_variant | Intron 28 of 65 | 2 | ENSP00000360885.4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Damages or destroys the splice donor site in intron 28, and is expected to cause abnormal gene splicing; if the splice outcome is exon skip, the loss of the encoded residues in the triple helical region is expected to disrupt normal protein folding and function (Symoens et al., 2012; HGMD); Published functional studies suggest aberrant splicing which leads to a frameshift and premature stop codon (Wenstrup et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22696272, 10777716) -
Ehlers-Danlos syndrome, classic type, 1 Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 28 of the COL5A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Ehlers-Danlos syndrome (PMID: 10777716, 22696272). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 409094). Studies have shown that disruption of this splice site results in inclusion of part of intron 28 and introduces a premature termination codon (PMID: 10777716). The resulting mRNA is expected to undergo nonsense-mediated decay. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at