4-5741785-T-C

Position:

chr4-5741785-T-C

Variant summary

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

The NM_153717.3(EVC):c.772T>C(p.Tyr258His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 1,539,220 control chromosomes in the GnomAD database, including 485,523 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 41669 hom., cov: 33)

Exomes 𝑓: 0.80 ( 443854 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.22

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=6.2664986E-7).

BP6

Variant 4-5741785-T-C is Benign according to our data. Variant chr4-5741785-T-C is described in ClinVar as [Benign]. Clinvar id is 198282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5741785-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.892 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.772T>C	p.Tyr258His	missense_variant	6/21	ENST00000264956.11	NP_714928.1	P57679

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11 linkuse as main transcript	c.772T>C	p.Tyr258His	missense_variant	6/21	1	NM_153717.3	ENSP00000264956.6		P57679
EVC	ENST00000509451.1 linkuse as main transcript	c.772T>C	p.Tyr258His	missense_variant	6/12	1		ENSP00000426774.1		E9PCN4

Frequencies

GnomAD3 genomes

AF:

0.729

AC:

110733

AN:

151944

Hom.:

41650

Cov.:

show subpopulations

Gnomad AFR

AF:

0.531

Gnomad AMI

AF:

0.773

Gnomad AMR

AF:

0.770

Gnomad ASJ

AF:

0.714

Gnomad EAS

AF:

0.913

Gnomad SAS

AF:

0.820

Gnomad FIN

AF:

0.869

Gnomad MID

AF:

0.660

Gnomad NFE

AF:

0.797

Gnomad OTH

AF:

0.739

GnomAD3 exomes

AF:

0.797

AC:

199019

AN:

249796

Hom.:

80173

AF XY:

0.800

AC XY:

108181

AN XY:

135160

show subpopulations

Gnomad AFR exome

AF:

0.527

Gnomad AMR exome

AF:

0.806

Gnomad ASJ exome

AF:

0.724

Gnomad EAS exome

AF:

0.907

Gnomad SAS exome

AF:

0.824

Gnomad FIN exome

AF:

0.860

Gnomad NFE exome

AF:

0.801

Gnomad OTH exome

AF:

0.790

GnomAD4 exome

AF:

0.797

AC:

1106102

AN:

1387158

Hom.:

443854

Cov.:

AF XY:

0.798

AC XY:

553714

AN XY:

694024

show subpopulations

Gnomad4 AFR exome

AF:

0.514

Gnomad4 AMR exome

AF:

0.806

Gnomad4 ASJ exome

AF:

0.726

Gnomad4 EAS exome

AF:

0.911

Gnomad4 SAS exome

AF:

0.824

Gnomad4 FIN exome

AF:

0.861

Gnomad4 NFE exome

AF:

0.799

Gnomad4 OTH exome

AF:

0.782

GnomAD4 genome

AF:

0.729

AC:

110782

AN:

152062

Hom.:

41669

Cov.:

AF XY:

0.734

AC XY:

54529

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.531

Gnomad4 AMR

AF:

0.770

Gnomad4 ASJ

AF:

0.714

Gnomad4 EAS

AF:

0.914

Gnomad4 SAS

AF:

0.821

Gnomad4 FIN

AF:

0.869

Gnomad4 NFE

AF:

0.798

Gnomad4 OTH

AF:

0.741

Alfa

AF:

0.784

Hom.:

107922

Bravo

AF:

0.713

TwinsUK

AF:

0.814

AC:

3020

ALSPAC

AF:

0.800

AC:

3083

ESP6500AA

AF:

0.519

AC:

2284

ESP6500EA

AF:

0.803

AC:

6902

ExAC

AF:

0.794

AC:

96328

Asia WGS

AF:

0.834

AC:

2893

AN:

3470

EpiCase

AF:

0.794

EpiControl

AF:

0.791

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2015	- -
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. -

Ellis-van Creveld syndrome

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.58

T;T

MetaRNN

Benign

6.3e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.033

Sift

Benign

0.43

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.0090

B;.

Vest4

0.077

ClinPred

0.0039

GERP RS

2.7

Varity_R

0.046

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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