rs33929747

chr4-5748276-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153717.3(EVC):c.1068A>G(p.Leu356=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 1,613,844 control chromosomes in the GnomAD database, including 83,732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6401 hom., cov: 32)
  • Exomes 𝑓: 0.32 (77331 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.912

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-5748276-A-G is Benign according to our data. Variant chr4-5748276-A-G is described in ClinVar as [Benign]. Clinvar id is 262762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5748276-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.912 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.1068A>G	p.Leu356=	synonymous_variant	8/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.1068A>G	p.Leu356=	synonymous_variant	8/21	1	NM_153717.3	P1
EVC	ENST00000509451.1	c.1068A>G	p.Leu356=	synonymous_variant	8/12	1
CRMP1	ENST00000506216.5	n.1684T>C		non_coding_transcript_exon_variant	13/13	5

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40538 AN: 151974 Hom.: 6406 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.291

GnomAD3 exomes AF: 0.298 AC: 74813 AN: 251348 Hom.: 12019 AF XY: 0.296 AC XY: 40148 AN XY: 135830

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.330

Gnomad ASJ exome AF: 0.404

Gnomad EAS exome AF: 0.187

Gnomad SAS exome AF: 0.191

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.350

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.319 AC: 466536 AN: 1461752 Hom.: 77331 Cov.: 49 AF XY: 0.316 AC XY: 229622 AN XY: 727166

Gnomad4 AFR exome AF: 0.0932

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.409

Gnomad4 EAS exome AF: 0.171

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.340

Gnomad4 OTH exome AF: 0.314

GnomAD4 genome AF: 0.267 AC: 40547 AN: 152092 Hom.: 6401 Cov.: 32 AF XY: 0.263 AC XY: 19533 AN XY: 74342

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.347

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.196

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.347

Gnomad4 OTH AF: 0.289

Alfa AF: 0.322 Hom.: 5851

Bravo AF: 0.264

Asia WGS AF: 0.176 AC: 615 AN: 3478

EpiCase AF: 0.354

EpiControl AF: 0.344

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ellis-van Creveld syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not specified Benign:2

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. -

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
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.1
Dann	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs33929747; hg19: chr4-5750003; COSMIC: COSV53830469; COSMIC: COSV53830469;