4-5711388-G-C

Position:

• chr4-5711388-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (8 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: 0.655

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052031577).
• BP6: Variant 4-5711388-G-C is Benign according to our data. Variant chr4-5711388-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193508.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

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: 280 AN: 148552 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000755

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000939

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00349

Gnomad OTH AF: 0.000978

GnomAD4 exome AF: 0.00398 AC: 3433 AN: 863436 Hom.: 8 Cov.: 29 AF XY: 0.00389 AC XY: 1569 AN XY: 402872

Gnomad4 AFR exome AF: 0.000306

Gnomad4 AMR exome AF: 0.00323

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000335

Gnomad4 NFE exome AF: 0.00428

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00188 AC: 280 AN: 148658 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 119 AN XY: 72514

Gnomad4 AFR AF: 0.000753

Gnomad4 AMR AF: 0.000938

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00349

Gnomad4 OTH AF: 0.000967

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.00198

ExAC AF: 0.000631 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	- -
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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -

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 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 26, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 02, 2024	Variant summary: EVC c.8G>C (p.Arg3Pro) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0037 in 1012094 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in EVC causing Ellis-van Creveld syndrome phenotype. c.8G>C has been reported in the literature as a heterozygous genotype in at-least two individuals within a cohort with known COL1A1/A2 gene variants and a diagnosis of Osteogenesis Imperfecta (OI) (Andersson_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Ellis-van Creveld syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32234057). ClinVar contains an entry for this variant (Variation ID: 193508). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

EVC-related disorder Benign:1

Likely benign, no assertion criteria provided

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.12
Sift	Benign	0.35	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.18
MVP		0.65
ClinPred		0.63	D
GERP RS		2.2
Varity_R		0.19
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs756852655; hg19: chr4-5713115;