rs587779671
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000090.4(COL3A1):c.582+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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_000090.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.582+5G>A | splice_region_variant, intron_variant | Intron 6 of 50 | 1 | NM_000090.4 | ENSP00000304408.4 | |||
COL3A1 | ENST00000450867.2 | c.582+5G>A | splice_region_variant, intron_variant | Intron 6 of 49 | 1 | ENSP00000415346.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Pathogenic:3
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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in several individuals affected with Ehlers-Danlos syndrome, vascular type (PMID: 24922459, 25758994, Invitae). ClinVar contains an entry for this variant (Variation ID: 101425). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 6 of the COL3A1 gene. It does not directly change the encoded amino acid sequence of the COL3A1 protein, but it affects a nucleotide within the consensus splice site of the intron. -
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Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The c.582+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 6 in the COL3A1 gene. This mutation has been reported in individuals with vascular Ehlers-Danlos syndrome (vEDS), including one reportedly de novo case (Pepin MG et al. Genet Med, 2014 Dec;16:881-8; Frank M et al. Eur J Hum Genet, 2015 Dec;23:1657-64; Legrand A et al. Genet Med, 2019 07;21:1568-1575). Additional intronic variants predicted to impact this donor site have also been reported in vEDS cohorts, including c.582+2dupT, c.582+5G>A, c.582+6T>A, and c.582+6T>C; exon 6 skipping was confirmed for the c.582+6T>C variant (Pepin MG et al. Genet Med, 2014 Dec;16:881-8; Lloyd J et al. J Med Genet, 1993 May;30:376-80). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
not provided Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at