4-5752852-C-T

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.1115C>T(p.Thr372Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.086 in 1,614,038 control chromosomes in the GnomAD database, including 6,743 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. T372T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.063 ( 449 hom., cov: 34)

Exomes 𝑓: 0.088 ( 6294 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.38

Publications

13 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=0.0014209151).

BP6

Variant 4-5752852-C-T is Benign according to our data. Variant chr4-5752852-C-T is described in ClinVar as [Benign]. Clinvar id is 262765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3 link	c.1115C>T	p.Thr372Met	missense_variant	Exon 9 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.1115C>T	p.Thr372Met	missense_variant	Exon 9 of 21	1	NM_153717.3	ENSP00000264956.6	P57679
EVC	ENST00000509451.1 link	c.1115C>T	p.Thr372Met	missense_variant	Exon 9 of 12	1		ENSP00000426774.1	E9PCN4
EVC	ENST00000514919.1 link	n.178C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
CRMP1	ENST00000506216.5 link	n.1648-4540G>A		intron_variant	Intron 12 of 12	5

Frequencies

GnomAD3 genomes

AF:

0.0631

AC:

9600

AN:

152190

Hom.:

450

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0167

Gnomad AMI

AF:

0.135

Gnomad AMR

AF:

0.0352

Gnomad ASJ

AF:

0.0801

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0400

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0927

Gnomad OTH

AF:

0.0521

GnomAD2 exomes

AF:

0.0673

AC:

16901

AN:

251260

AF XY:

0.0691

show subpopulations

Gnomad AFR exome

AF:

0.0158

Gnomad AMR exome

AF:

0.0276

Gnomad ASJ exome

AF:

0.0783

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.121

Gnomad NFE exome

AF:

0.0930

Gnomad OTH exome

AF:

0.0694

GnomAD4 exome

AF:

0.0884

AC:

129174

AN:

1461730

Hom.:

6294

Cov.:

AF XY:

0.0872

AC XY:

63411

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.0155

AC:

519

AN:

33480

American (AMR)

AF:

0.0282

AC:

1262

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0796

AC:

2080

AN:

26136

East Asian (EAS)

AF:

0.000327

AC:

AN:

39698

South Asian (SAS)

AF:

0.0421

AC:

3629

AN:

86258

European-Finnish (FIN)

AF:

0.120

AC:

6423

AN:

53414

Middle Eastern (MID)

AF:

0.0437

AC:

252

AN:

5768

European-Non Finnish (NFE)

AF:

0.0992

AC:

110333

AN:

1111858

Other (OTH)

AF:

0.0772

AC:

4663

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

6750

13500

20250

27000

33750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3984

7968

11952

15936

19920

<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:

0.0630

AC:

9601

AN:

152308

Hom.:

449

Cov.:

AF XY:

0.0630

AC XY:

4688

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0167

AC:

694

AN:

41574

American (AMR)

AF:

0.0351

AC:

538

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0801

AC:

278

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.0400

AC:

193

AN:

4824

European-Finnish (FIN)

AF:

0.127

AC:

1352

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0926

AC:

6301

AN:

68012

Other (OTH)

AF:

0.0530

AC:

112

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

461

922

1382

1843

2304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

224

336

448

560

<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:

0.0817

Hom.:

1034

Bravo

AF:

0.0548

TwinsUK

AF:

0.0992

AC:

368

ALSPAC

AF:

0.107

AC:

412

ESP6500AA

AF:

0.0202

AC:

ESP6500EA

AF:

0.0898

AC:

772

ExAC

AF:

0.0674

AC:

8178

Asia WGS

AF:

0.0280

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ellis-van Creveld syndrome

Benign:3

Jan 12, 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. -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 26, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Oct 29, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.76

T;D

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

1.4

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.060

Sift

Benign

0.22

T;T

Sift4G

Benign

0.36

T;D

Polyphen

0.97

D;.

Vest4

0.13

ClinPred

0.016

GERP RS

3.8

Varity_R

0.049

gMVP

0.17

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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