4-5753797-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153717.3(EVC):c.1328G>A(p.Arg443Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,614,078 control chromosomes in the GnomAD database, including 2,137 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R443R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.067 ( 1127 hom., cov: 34)

Exomes 𝑓: 0.0072 ( 1010 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:13

Conservation

PhyloP100: 0.112

Publications

11 publications found

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012990832).

BP6

Variant 4-5753797-G-A is Benign according to our data. Variant chr4-5753797-G-A is described in ClinVar as Benign. ClinVar VariationId is 5342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3 link	c.1328G>A	p.Arg443Gln	missense_variant	Exon 10 of 21	ENST00000264956.11	NP_714928.1	P57679

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EVC	ENST00000264956.11 link	c.1328G>A	p.Arg443Gln	missense_variant	Exon 10 of 21	1	NM_153717.3	ENSP00000264956.6	P57679
EVC	ENST00000509451.1 link	c.1328G>A	p.Arg443Gln	missense_variant	Exon 10 of 12	1		ENSP00000426774.1	E9PCN4
EVC	ENST00000514919.1 link	n.391G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
CRMP1	ENST00000506216.5 link	n.1648-5485C>T		intron_variant	Intron 12 of 12	5

Frequencies

GnomAD3 genomes

AF:

0.0665

AC:

10108

AN:

152114

Hom.:

1122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.226

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0345

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.0555

GnomAD2 exomes

AF:

0.0176

AC:

4418

AN:

251456

AF XY:

0.0129

show subpopulations

Gnomad AFR exome

AF:

0.232

Gnomad AMR exome

AF:

0.0124

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.00720

AC:

10530

AN:

1461846

Hom.:

1010

Cov.:

AF XY:

0.00626

AC XY:

4549

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.235

AC:

7864

AN:

33476

American (AMR)

AF:

0.0141

AC:

630

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000580

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000769

AC:

855

AN:

1111994

Other (OTH)

AF:

0.0172

AC:

1039

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

541

1082

1623

2164

2705

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

244

488

732

976

1220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0666

AC:

10140

AN:

152232

Hom.:

1127

Cov.:

AF XY:

0.0643

AC XY:

4787

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.226

AC:

9401

AN:

41512

American (AMR)

AF:

0.0344

AC:

527

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

68028

Other (OTH)

AF:

0.0549

AC:

116

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

407

815

1222

1630

2037

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0274

Hom.:

1068

Bravo

AF:

0.0778

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.225

AC:

991

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.0210

AC:

2553

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00184

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

Jan 11, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 16, 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

Uncertain:1Benign:3

Sep 12, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2000

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 30, 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

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.082

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.75

T;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

PhyloP100

0.11

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.53

N;N

REVEL

Benign

0.058

Sift

Benign

0.71

T;T

Sift4G

Benign

0.80

T;T

Polyphen

0.27

B;.

Vest4

0.079

ClinPred

0.0067

GERP RS

1.1

Varity_R

0.042

gMVP

0.049

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over