chr4-5793685-C-T

Variant names:

• chr4-5793685-C-T
• rs11737221
• NM_153717.3:c.1854C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153717.3(EVC):​c.1854C>T​(p.Gly618Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,550,636 control chromosomes in the GnomAD database, including 87,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G618G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (6782 hom., cov: 32)
  • Exomes 𝑓: 0.33 (80949 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.80
• Publications: 21 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 4-5793685-C-T is Benign according to our data. Variant chr4-5793685-C-T is described in ClinVar as Benign. ClinVar VariationId is 262769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153717.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	NM_153717.3	MANE Select	c.1854C>T	p.Gly618Gly	synonymous	Exon 13 of 21	NP_714928.1
	EVC	NM_001306090.2		c.1854C>T	p.Gly618Gly	synonymous	Exon 13 of 21	NP_001293019.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	ENST00000264956.11	TSL:1 MANE Select	c.1854C>T	p.Gly618Gly	synonymous	Exon 13 of 21	ENSP00000264956.6
	EVC	ENST00000506240.1	TSL:3	n.172C>T		non_coding_transcript_exon	Exon 1 of 2
	EVC	ENST00000515113.1	TSL:5	n.78C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41578 AN: 151892 Hom.: 6776 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.284

GnomAD2 exomes AF: 0.355 AC: 55868 AN: 157544 AF XY: 0.369

Gnomad AFR exome AF: 0.0953

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.514

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.337

GnomAD4 exome AF: 0.333 AC: 465360 AN: 1398626 Hom.: 80949 Cov.: 37 AF XY: 0.339 AC XY: 233910 AN XY: 689968

African (AFR) AF: 0.0979 AC: 3108 AN: 31738

American (AMR) AF: 0.341 AC: 12223 AN: 35866

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 7660 AN: 25184

East Asian (EAS) AF: 0.504 AC: 18100 AN: 35884

South Asian (SAS) AF: 0.520 AC: 41229 AN: 79214

European-Finnish (FIN) AF: 0.319 AC: 15743 AN: 49354

Middle Eastern (MID) AF: 0.333 AC: 1448 AN: 4354

European-Non Finnish (NFE) AF: 0.321 AC: 346699 AN: 1079140

Other (OTH) AF: 0.331 AC: 19150 AN: 57892

GnomAD4 genome AF: 0.274 AC: 41603 AN: 152010 Hom.: 6782 Cov.: 32 AF XY: 0.283 AC XY: 21037 AN XY: 74272

African (AFR) AF: 0.103 AC: 4265 AN: 41508

American (AMR) AF: 0.318 AC: 4863 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1075 AN: 3472

East Asian (EAS) AF: 0.518 AC: 2657 AN: 5134

South Asian (SAS) AF: 0.534 AC: 2565 AN: 4804

European-Finnish (FIN) AF: 0.319 AC: 3366 AN: 10546

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21812 AN: 67958

Other (OTH) AF: 0.282 AC: 596 AN: 2116

Alfa AF: 0.224 Hom.: 1410

Bravo AF: 0.265

Asia WGS AF: 0.481 AC: 1671 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Ellis-van Creveld syndrome Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:2

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Curry-Hall syndrome Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.7
DANN	Benign	0.80
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11737221; hg19: chr4-5795412; COSMIC: COSV53832761;