4-5793657-G-A

Position:

• chr4-5793657-G-A

Variant summary

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

The NM_153717.3(EVC):​c.1826G>A​(p.Arg609Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,553,106 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R609W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (6 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: -0.0260

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005234629).
• BP6: Variant 4-5793657-G-A is Benign according to our data. Variant chr4-5793657-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194282.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}. Variant chr4-5793657-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.1826G>A	p.Arg609Gln	missense_variant	13/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.1826G>A	p.Arg609Gln	missense_variant	13/21	1	NM_153717.3	P1
EVC	ENST00000506240.1	n.144G>A		non_coding_transcript_exon_variant	1/2	3
EVC	ENST00000515113.1	n.50G>A		non_coding_transcript_exon_variant	1/4	5
CRMP1	ENST00000506216.5	n.1647+31837C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00343

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00173 AC: 276 AN: 159774 Hom.: 0 AF XY: 0.00175 AC XY: 147 AN XY: 84206

Gnomad AFR exome AF: 0.000867

Gnomad AMR exome AF: 0.000758

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000581

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.000447

GnomAD4 exome AF: 0.00319 AC: 4470 AN: 1400824 Hom.: 6 Cov.: 30 AF XY: 0.00314 AC XY: 2169 AN XY: 691078

Gnomad4 AFR exome AF: 0.000408

Gnomad4 AMR exome AF: 0.000638

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000167

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.000850

Gnomad4 NFE exome AF: 0.00393

Gnomad4 OTH exome AF: 0.00247

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74464

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00343

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00331 Hom.: 1

Bravo AF: 0.00198

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000923 AC: 4

ESP6500EA AF: 0.00296 AC: 25

ExAC AF: 0.000920 AC: 95

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 17, 2023	Variant summary: EVC c.1826G>A (p.Arg609Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 159774 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1826G>A in individuals affected with Ellis-van Creveld syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS(n=6) and likely benign(n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 27, 2019	The EVC c.1826G>A; p.Arg609Gln variant (rs41269557), to our knowledge, is not described in the medical literature but is reported as likely benign by several laboratories in ClinVar (Variation ID: 194282). It is observed in the general population at an overall frequency of 0.17% (314/183408 alleles) with increased frequency in the European (Non-Finnish) population (0.36%) in the Genome Aggregation Database. The arginine at codon 609 is weakly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. Pathogenic EVC variants are inherited in an autosomal recessive manner associated with Ellis-van Creveld syndrome (MIM: 225500) and in an autosomal dominant manner associated with Weyers acrodental dysostosis (MIM: 193530). -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	EVC: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2021	- -

Ellis-van Creveld syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

The c.1826G>A (p.R609Q) alteration is located in exon 13 (coding exon 13) of the EVC gene. This alteration results from a G to A substitution at nucleotide position 1826, causing the arginine (R) at amino acid position 609 to be replaced by a glutamine (Q). 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 31, 2024

- -

EVC-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 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	0.070
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.30	T
Sift4G	Benign	0.32	T
Polyphen		0.022	B
Vest4		0.17
MVP		0.39
ClinPred		0.021	T
GERP RS		1.2
Varity_R		0.027
gMVP		0.081

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: rs41269557; hg19: chr4-5795384;