chr4-5719294-A-C

Position:

chr4-5719294-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000264956.11(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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin 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
ENST00000264956.11 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.24

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
EVC	NM_153717.3 linkuse as main transcript	c.221A>C	p.Gln74Pro	missense_variant	2/21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11 linkuse as main transcript	c.221A>C	p.Gln74Pro	missense_variant	2/21	1	NM_153717.3	ENSP00000264956	P1
EVC	ENST00000509451.1 linkuse as main transcript	c.221A>C	p.Gln74Pro	missense_variant	2/12	1		ENSP00000426774

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

GnomAD3 exomes

AF:

0.110

AC:

27699

AN:

251486

Hom.:

1803

AF XY:

0.110

AC XY:

14975

AN XY:

135914

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 SAS exome

AF:

0.146

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

Gnomad4 AFR exome

AF:

0.0496

Gnomad4 AMR exome

AF:

0.171

Gnomad4 ASJ exome

AF:

0.138

Gnomad4 EAS exome

AF:

0.150

Gnomad4 SAS exome

AF:

0.146

Gnomad4 FIN exome

AF:

0.0553

Gnomad4 NFE exome

AF:

0.0845

Gnomad4 OTH exome

AF:

0.0973

GnomAD4 genome

AF:

0.0830

AC:

12634

AN:

152264

Hom.:

640

Cov.:

AF XY:

0.0838

AC XY:

6243

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0472

Gnomad4 AMR

AF:

0.123

Gnomad4 ASJ

AF:

0.141

Gnomad4 EAS

AF:

0.170

Gnomad4 SAS

AF:

0.141

Gnomad4 FIN

AF:

0.0575

Gnomad4 NFE

AF:

0.0856

Gnomad4 OTH

AF:

0.0903

Alfa

AF:

0.0909

Hom.:

1382

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

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	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 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	-	- -

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

- -

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

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;.

MutationTaster

Benign

1.0

P;P;P

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

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

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