rs587779535
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000090.4(COL3A1):c.1662+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,314 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 Pathogenic (★★).
Frequency
Consequence
NM_000090.4 splice_donor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL3A1 | NM_000090.4 | c.1662+1G>A | splice_donor_variant | ENST00000304636.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.1662+1G>A | splice_donor_variant | 1 | NM_000090.4 | P1 | |||
COL3A1 | ENST00000450867.2 | c.1563+1G>A | splice_donor_variant | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461314Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727000
GnomAD4 genome ? Cov.: 30
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2022 | ClinVar contains an entry for this variant (Variation ID: 101269). This variant is also known as IVS24+1G>A. Disruption of this splice site has been observed in individuals with Ehlers-Danlos syndrome (EDS), vascular type (PMID: 8881656, 9399899, 21533953, 25758994). This variant is present in population databases (rs587779535, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 23 of the COL3A1 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 COL3A1 are known to be pathogenic (PMID: 24922459). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Collagen Diagnostic Laboratory, University of Washington | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000101269). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 06, 2017 | c.1662+1 G>A: IVS23+1 G>A in intron 23 of the COL3A1 gene (NM_000090.3) The c.1662+1 G>A mutation has been reported multiple times in association with EDS type IV (often reported as IVS24+1 G>A due to alternate nomenclature; Pope et al., 1996; Pepin et al., 2000; Omori et al., 2011; Pepin et al., 2014). This mutation destroys the canonical splice donor site in intron 23 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations in the COL3A1 gene have been reported in association with EDS type IV. Furthermore, the c.1662+1 G>A mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.1662+1 G>A in the COL3A1 gene is interpreted as a disease-causing mutation. The variant is found in TAAD panel(s). - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 12, 2017 | The c.1662+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 23 of the COL3A1 gene. This alteration, previously referred to as IVS 24+1 G>A, has been reported in multiple unrelated individuals with Ehlers-Danlos syndrome and shown to cause exon 23 skipping (Pope FM et al. Br. J. Dermatol., 1996 Aug;135:163-81; Schwarze U et al. Am. J. Hum. Genet., 1997 Dec;61:1276-86; Omori H et al. Surg. Today, 2011 May;41:733-6; Frank M et al. Eur. J. Hum. Genet., 2015 Dec;23:1657-64). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at