rs794726665
Variant names:
Your query was ambiguous. Multiple possible variants found:
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
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000029 ( 0 hom. )
Consequence
EVC
NM_153717.3 splice_region, intron
NM_153717.3 splice_region, intron
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.01
Genes affected
EVC (HGNC:3497): (EvC ciliary complex subunit 1) This gene encodes a protein containing a leucine zipper and a transmembrane domain. This gene has been implicated in both Ellis-van Creveld syndrome (EvC) and Weyers acrodental dysostosis. [provided by RefSeq, Jul 2008]
CRMP1 (HGNC:2365): (collapsin response mediator protein 1) This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-5793722-G-A is Pathogenic according to our data. Variant chr4-5793722-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1458810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5793722-G-A is described in Lovd as [Pathogenic].
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
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GnomAD3 exomes AF: 0.00000646 AC: 1AN: 154720Hom.: 0 AF XY: 0.0000122 AC XY: 1AN XY: 81766
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GnomAD4 exome AF: 0.00000287 AC: 4AN: 1395078Hom.: 0 Cov.: 30 AF XY: 0.00000436 AC XY: 3AN XY: 688218
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74366
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 27, 2021 | 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
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2023 | 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:
Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at