4-5711388-G-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_153717.3(EVC):c.8G>C(p.Arg3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,012,094 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R3R) has been classified as Likely benign.
Frequency
Consequence
NM_153717.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EVC | NM_153717.3 | c.8G>C | p.Arg3Pro | missense_variant | 1/21 | ENST00000264956.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EVC | ENST00000264956.11 | c.8G>C | p.Arg3Pro | missense_variant | 1/21 | 1 | NM_153717.3 | P1 | |
EVC | ENST00000509451.1 | c.8G>C | p.Arg3Pro | missense_variant | 1/12 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00188 AC: 280AN: 148552Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00398 AC: 3433AN: 863436Hom.: 8 Cov.: 29 AF XY: 0.00389 AC XY: 1569AN XY: 402872
GnomAD4 genome ? AF: 0.00188 AC: 280AN: 148658Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 119AN XY: 72514
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 16, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 04, 2020 | The EVC c.8G>C; p.Arg3Pro (rs756852655), to our knowledge, is not described in the medical literature but is reported as a variant of uncertain clinical significance in ClinVar (Variation ID 193508) and is observed in the general population at an overall allele frequency of 0.17% (45/26668 alleles) in the Genome Aggregation Database. The arginine at codon 3 is weakly conserved and computational algorithms (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure and/or function. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. Pathogenic EVC variants are associated with autosomal recessive Ellis-van Creveld syndrome (MIM:225500) and autosomal dominant Weyers acrodental dysostosis (MIM:193530). - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 18, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | - - |
Ellis-van Creveld syndrome Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 26, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2021 | The c.8G>C (p.R3P) alteration is located in exon 1 (coding exon 1) of the EVC gene. This alteration results from a G to C substitution at nucleotide position 8, causing the arginine (R) at amino acid position 3 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
EVC-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 29, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at