rs41269547

Positions:

chr4-5719357-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_153717.3(EVC):c.284A>G(p.Asp95Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00588 in 1,614,184 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 39 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:14

Conservation

PhyloP100: 1.86

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044302642).

BP6

Variant 4-5719357-A-G is Benign according to our data. Variant chr4-5719357-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 195425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5719357-A-G is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC	NM_153717.3 linkuse as main transcript	c.284A>G	p.Asp95Gly	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.284A>G	p.Asp95Gly	missense_variant	2/21	1	NM_153717.3	ENSP00000264956	P1
EVC	ENST00000509451.1 linkuse as main transcript	c.284A>G	p.Asp95Gly	missense_variant	2/12	1		ENSP00000426774

Frequencies

GnomAD3 genomes

AF:

0.00543

AC:

826

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00829

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00808

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00609

AC:

1530

AN:

251320

Hom.:

AF XY:

0.00616

AC XY:

837

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.0246

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00910

Gnomad NFE exome

AF:

0.00818

Gnomad OTH exome

AF:

0.00782

GnomAD4 exome

AF:

0.00593

AC:

8670

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00588

AC XY:

4279

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00291

Gnomad4 ASJ exome

AF:

0.0268

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.0104

Gnomad4 NFE exome

AF:

0.00615

Gnomad4 OTH exome

AF:

0.00599

GnomAD4 genome

AF:

0.00542

AC:

826

AN:

152316

Hom.:

Cov.:

AF XY:

0.00544

AC XY:

405

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000842

Gnomad4 AMR

AF:

0.00385

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00829

Gnomad4 NFE

AF:

0.00809

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00768

Hom.:

Bravo

AF:

0.00454

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.00601

AC:

730

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00769

EpiControl

AF:

0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2018	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	Genetic Services Laboratory, University of Chicago	Feb 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 14, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 13, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	EVC: BP4, BS2 -

Ellis-van Creveld syndrome

Benign:3

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 04, 2019	- -

Nephronophthisis

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Oct 25, 2018

This patient is heterozygous for a variant of unknown clinical significance (VOUS), c.284A>G p.(Asp95Gly) in the EVC gene. To our knowledge, this variant has not been previously reported in the literature. However, this variant has been reported in dbSNP (rs4126957) with a minor allele frequency (MAF) of 0.0067 in the European American population (n=8600). In silico analysis (Alamut Visual v2.4) is inconclusive regarding this variant, Align GVGD, MutationTaster and KD4v predicts it to be benign whereas PolyPhen2 and SIFT predicts it to be pathogenic. Alamut v2.4 also predicts this variant does not affect splicing. -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.59

T;T

MetaRNN

Benign

0.0044

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.0

M;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.12

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

0.99

D;.

Vest4

0.34

MVP

0.69

ClinPred

0.027

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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