rs4688963

Variant names:

• chr4-5748177-T-C
• rs4688963
• NM_153717.3:c.969T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_153717.3(EVC):​c.969T>C​(p.Asn323Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 1,613,814 control chromosomes in the GnomAD database, including 132,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13248 hom., cov: 33)
  • Exomes 𝑓: 0.40 (119027 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.892
• Publications: 25 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 4-5748177-T-C is Benign according to our data. Variant chr4-5748177-T-C is described in ClinVar as Benign. ClinVar VariationId is 262786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.892 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3	c.969T>C	p.Asn323Asn	synonymous_variant	Exon 8 of 21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.969T>C	p.Asn323Asn	synonymous_variant	Exon 8 of 21	1	NM_153717.3	ENSP00000264956.6
EVC	ENST00000509451.1	c.969T>C	p.Asn323Asn	synonymous_variant	Exon 8 of 12	1		ENSP00000426774.1
CRMP1	ENST00000506216.5	n.1783A>G		non_coding_transcript_exon_variant	Exon 13 of 13	5

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62557 AN: 151918 Hom.: 13226 Cov.: 33

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.354

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.531

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.413 AC: 103901 AN: 251444 AF XY: 0.419

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.340

Gnomad ASJ exome AF: 0.358

Gnomad EAS exome AF: 0.624

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.377

GnomAD4 exome AF: 0.399 AC: 582821 AN: 1461778 Hom.: 119027 Cov.: 50 AF XY: 0.403 AC XY: 292996 AN XY: 727196

African (AFR) AF: 0.475 AC: 15917 AN: 33476

American (AMR) AF: 0.338 AC: 15136 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 9284 AN: 26134

East Asian (EAS) AF: 0.642 AC: 25476 AN: 39700

South Asian (SAS) AF: 0.538 AC: 46407 AN: 86254

European-Finnish (FIN) AF: 0.391 AC: 20877 AN: 53392

Middle Eastern (MID) AF: 0.392 AC: 2259 AN: 5768

European-Non Finnish (NFE) AF: 0.380 AC: 422955 AN: 1111934

Other (OTH) AF: 0.406 AC: 24510 AN: 60396

GnomAD4 genome AF: 0.412 AC: 62625 AN: 152036 Hom.: 13248 Cov.: 33 AF XY: 0.417 AC XY: 30966 AN XY: 74304

African (AFR) AF: 0.472 AC: 19586 AN: 41458

American (AMR) AF: 0.345 AC: 5276 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.354 AC: 1228 AN: 3470

East Asian (EAS) AF: 0.626 AC: 3230 AN: 5158

South Asian (SAS) AF: 0.532 AC: 2559 AN: 4810

European-Finnish (FIN) AF: 0.408 AC: 4303 AN: 10546

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25121 AN: 67992

Other (OTH) AF: 0.397 AC: 836 AN: 2108

Alfa AF: 0.378 Hom.: 17509

Bravo AF: 0.410

Asia WGS AF: 0.549 AC: 1909 AN: 3478

EpiCase AF: 0.369

EpiControl AF: 0.380

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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. -

Ellis-van Creveld syndrome Benign:3

Jun 15, 2021

Pars Genome 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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.76
PhyloP100		0.89
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: rs4688963; hg19: chr4-5749904; COSMIC: COSV53833510; COSMIC: COSV53833510;