rs794726665
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_153717.3(EVC):c.1886+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000323 in 1,547,298 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (★★).
Frequency
Consequence
NM_153717.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EVC | ENST00000264956.11 | c.1886+5G>A | splice_region_variant, intron_variant | Intron 13 of 20 | 1 | NM_153717.3 | ENSP00000264956.6 | |||
CRMP1 | ENST00000506216.5 | n.1647+31772C>T | intron_variant | Intron 12 of 12 | 5 | |||||
EVC | ENST00000506240.1 | n.204+5G>A | splice_region_variant, intron_variant | Intron 1 of 1 | 3 | |||||
EVC | ENST00000515113.1 | n.110+5G>A | splice_region_variant, intron_variant | Intron 1 of 3 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000646 AC: 1AN: 154720Hom.: 0 AF XY: 0.0000122 AC XY: 1AN XY: 81766
GnomAD4 exome AF: 0.00000287 AC: 4AN: 1395078Hom.: 0 Cov.: 30 AF XY: 0.00000436 AC XY: 3AN XY: 688218
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74366
ClinVar
Submissions by phenotype
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:1
This variant is also known as IVS13+5G>A. This sequence change falls in intron 13 of the EVC gene. It does not directly change the encoded amino acid sequence of the EVC protein. It affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with Ellis-van Creveld syndrome (PMID: 23220543, 23924873). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 23220543). This variant disrupts the c.1886+5 nucleotide in the EVC gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10700184, 17024374, 23220543, 31028937). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 29068549, 10700184, 17024374, 23220543, 23924873, 26582918) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at