4-5810453-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_153717.3(EVC):c.2894+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_153717.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000851 AC: 2AN: 235092Hom.: 0 AF XY: 0.00000788 AC XY: 1AN XY: 126934
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1454804Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 722998
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Ellis-van Creveld syndrome Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 09, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Dec 09, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 10, 2021 | NM_153717.2(EVC):c.2894+3A>G is an intronic variant classified as likely pathogenic in the context of EVC-related Ellis-van Creveld syndrome. c.2894+3A>G has been observed in cases with relevant disease (PMID: 23220543, 29321360). Functional assessments of this variant are available in the literature (PMID: 23220543). c.2894+3A>G has been observed in population frequency databases (gnomAD: NFE 0.002%). In summary, NM_153717.2(EVC):c.2894+3A>G is an intronic variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 16, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 09, 2024 | This sequence change falls in intron 20 of the EVC gene. It does not directly change the encoded amino acid sequence of the EVC protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individuals with Ellis-van Creveld syndrome (PMID: 23220543, 29321360; internal data). ClinVar contains an entry for this variant (Variation ID: 488510). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 20 and introduces a new termination codon (PMID: 23220543). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Feb 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at