chr4-5719294-A-C

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.221A>C(p.Gln74Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0915 in 1,614,118 control chromosomes in the GnomAD database, including 7,525 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q74Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.083 ( 640 hom., cov: 32)

Exomes 𝑓: 0.092 ( 6885 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.24

Publications

26 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 Gene-Disease associations (from GenCC):

acrofacial dysostosis, Weyers type
Inheritance: AD, Unknown, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
Ellis-van Creveld syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health

EVC 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=0.0013287067).

BP6

Variant 4-5719294-A-C is Benign according to our data. Variant chr4-5719294-A-C is described in ClinVar as Benign. ClinVar VariationId is 262770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3 link	c.221A>C	p.Gln74Pro	missense_variant	Exon 2 of 21	ENST00000264956.11	NP_714928.1	P57679

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11 link	c.221A>C	p.Gln74Pro	missense_variant	Exon 2 of 21	1	NM_153717.3	ENSP00000264956.6		P57679
EVC	ENST00000509451.1 link	c.221A>C	p.Gln74Pro	missense_variant	Exon 2 of 12	1		ENSP00000426774.1		E9PCN4

Frequencies

GnomAD3 genomes

AF:

0.0831

AC:

12641

AN:

152146

Hom.:

642

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0472

Gnomad AMI

AF:

0.0746

Gnomad AMR

AF:

0.123

Gnomad ASJ

AF:

0.141

Gnomad EAS

AF:

0.170

Gnomad SAS

AF:

0.141

Gnomad FIN

AF:

0.0575

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.0856

Gnomad OTH

AF:

0.0912

GnomAD2 exomes

AF:

0.110

AC:

27699

AN:

251486

AF XY:

0.110

show subpopulations

Gnomad AFR exome

AF:

0.0459

Gnomad AMR exome

AF:

0.178

Gnomad ASJ exome

AF:

0.140

Gnomad EAS exome

AF:

0.175

Gnomad FIN exome

AF:

0.0544

Gnomad NFE exome

AF:

0.0865

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.0924

AC:

135073

AN:

1461854

Hom.:

6885

Cov.:

AF XY:

0.0934

AC XY:

67919

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0496

AC:

1662

AN:

33480

American (AMR)

AF:

0.171

AC:

7637

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

3604

AN:

26136

East Asian (EAS)

AF:

0.150

AC:

5966

AN:

39696

South Asian (SAS)

AF:

0.146

AC:

12619

AN:

86258

European-Finnish (FIN)

AF:

0.0553

AC:

2953

AN:

53418

Middle Eastern (MID)

AF:

0.143

AC:

824

AN:

5768

European-Non Finnish (NFE)

AF:

0.0845

AC:

93931

AN:

1111986

Other (OTH)

AF:

0.0973

AC:

5877

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

7659

15319

22978

30638

38297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3634

7268

10902

14536

18170

<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:

0.0830

AC:

12634

AN:

152264

Hom.:

640

Cov.:

AF XY:

0.0838

AC XY:

6243

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0472

AC:

1962

AN:

41558

American (AMR)

AF:

0.123

AC:

1876

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.141

AC:

491

AN:

3472

East Asian (EAS)

AF:

0.170

AC:

881

AN:

5168

South Asian (SAS)

AF:

0.141

AC:

679

AN:

4812

European-Finnish (FIN)

AF:

0.0575

AC:

611

AN:

10620

Middle Eastern (MID)

AF:

0.173

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0856

AC:

5824

AN:

68020

Other (OTH)

AF:

0.0903

AC:

191

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

598

1195

1793

2390

2988

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.0898

Hom.:

1948

Bravo

AF:

0.0893

TwinsUK

AF:

0.0863

AC:

320

ALSPAC

AF:

0.0823

AC:

317

ESP6500AA

AF:

0.0506

AC:

223

ESP6500EA

AF:

0.0921

AC:

792

ExAC

AF:

0.108

AC:

13099

Asia WGS

AF:

0.127

AC:

441

AN:

3478

EpiCase

AF:

0.0875

EpiControl

AF:

0.0916

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ellis-van Creveld syndrome

Benign:3

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

- -

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 specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 21, 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;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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.50

T;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

M;.

PhyloP100

1.2

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.085

Sift

Benign

0.051

T;T

Sift4G

Uncertain

0.020

D;D

Polyphen

0.011

B;.

Vest4

0.23

ClinPred

0.0036

GERP RS

-0.093

Varity_R

0.25

gMVP

0.22

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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