rs4688963

Positions:

chr4-5748177-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_153717.3(EVC):c.969T>C(p.Asn323=) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.892

Variant links:

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]

EVC links:

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]

CRMP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 262786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5748177-T-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
EVC	NM_153717.3 linkuse as main transcript	c.969T>C	p.Asn323=	synonymous_variant	8/21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
EVC	ENST00000264956.11 linkuse as main transcript	c.969T>C	p.Asn323=	synonymous_variant	8/21	1	NM_153717.3	ENSP00000264956	P1
EVC	ENST00000509451.1 linkuse as main transcript	c.969T>C	p.Asn323=	synonymous_variant	8/12	1		ENSP00000426774
CRMP1	ENST00000506216.5 linkuse as main transcript	n.1783A>G		non_coding_transcript_exon_variant	13/13	5

Frequencies

GnomAD3 genomes

AF:

0.412

AC:

62557

AN:

151918

Hom.:

13226

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.413

AC:

103901

AN:

251444

Hom.:

22347

AF XY:

0.419

AC XY:

56994

AN XY:

135900

show subpopulations

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 SAS exome

AF:

0.536

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.:

AF XY:

0.403

AC XY:

292996

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.475

Gnomad4 AMR exome

AF:

0.338

Gnomad4 ASJ exome

AF:

0.355

Gnomad4 EAS exome

AF:

0.642

Gnomad4 SAS exome

AF:

0.538

Gnomad4 FIN exome

AF:

0.391

Gnomad4 NFE exome

AF:

0.380

Gnomad4 OTH exome

AF:

0.406

GnomAD4 genome

AF:

0.412

AC:

62625

AN:

152036

Hom.:

13248

Cov.:

AF XY:

0.417

AC XY:

30966

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.472

Gnomad4 AMR

AF:

0.345

Gnomad4 ASJ

AF:

0.354

Gnomad4 EAS

AF:

0.626

Gnomad4 SAS

AF:

0.532

Gnomad4 FIN

AF:

0.408

Gnomad4 NFE

AF:

0.369

Gnomad4 OTH

AF:

0.397

Alfa

AF:

0.377

Hom.:

14075

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

LINK: link

Submissions by phenotype

not specified

Benign:4

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Ellis-van Creveld syndrome

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

-0.43

CADD

Benign

DANN

Benign

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over