rs1383180

chr4-5783715-G-Achr4-5783715-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153717.3(EVC):c.1727G>A(p.Arg576Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,613,550 control chromosomes in the GnomAD database, including 99,274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R576L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (8380 hom., cov: 32)
  • Exomes 𝑓: 0.35 (90894 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.16

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028758347).
• BP6: Variant 4-5783715-G-A is Benign according to our data. Variant chr4-5783715-G-A is described in ClinVar as [Benign]. Clinvar id is 262768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5783715-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.1727G>A	p.Arg576Gln	missense_variant	12/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.1727G>A	p.Arg576Gln	missense_variant	12/21	1	NM_153717.3	P1
CRMP1	ENST00000506216.5	n.1648-35403C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48777 AN: 151962 Hom.: 8380 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.329

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.349 AC: 87463 AN: 250448 Hom.: 16091 AF XY: 0.342 AC XY: 46258 AN XY: 135398

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.493

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.310

Gnomad SAS exome AF: 0.222

Gnomad FIN exome AF: 0.339

Gnomad NFE exome AF: 0.367

Gnomad OTH exome AF: 0.364

GnomAD4 exome AF: 0.349 AC: 509331 AN: 1461470 Hom.: 90894 Cov.: 54 AF XY: 0.345 AC XY: 250549 AN XY: 727026

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.488

Gnomad4 ASJ exome AF: 0.387

Gnomad4 EAS exome AF: 0.306

Gnomad4 SAS exome AF: 0.227

Gnomad4 FIN exome AF: 0.340

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.321 AC: 48781 AN: 152080 Hom.: 8380 Cov.: 32 AF XY: 0.319 AC XY: 23692 AN XY: 74344

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.444

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.315

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.329

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.339

Alfa AF: 0.360 Hom.: 24610

Bravo AF: 0.324

TwinsUK AF: 0.355 AC: 1316

ALSPAC AF: 0.369 AC: 1423

ESP6500AA AF: 0.198 AC: 871

ESP6500EA AF: 0.365 AC: 3135

ExAC AF: 0.339 AC: 41118

Asia WGS AF: 0.252 AC: 878 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Ellis-van Creveld syndrome Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Curry-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	0.084	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.16
Sift	Benign	0.12	T
Sift4G	Benign	0.085	T
Polyphen		1.0	D
Vest4		0.20
ClinPred		0.018	T
GERP RS		4.1
Varity_R		0.097
gMVP		0.29

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: rs1383180; hg19: chr4-5785442; COSMIC: COSV53832754;