rs41269547

chr4-5719357-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:14
• Conservation: PhyloP100: 1.86

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]

ACMG classification

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 GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.284A>G	p.Asp95Gly	missense_variant	2/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.284A>G	p.Asp95Gly	missense_variant	2/21	1	NM_153717.3	P1
EVC	ENST00000509451.1	c.284A>G	p.Asp95Gly	missense_variant	2/12	1

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152198 Hom.: 3 Cov.: 32

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.: 8 AF XY: 0.00616 AC XY: 837 AN XY: 135830

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.: 39 Cov.: 33 AF XY: 0.00588 AC XY: 4279 AN XY: 727240

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.: 3 Cov.: 32 AF XY: 0.00544 AC XY: 405 AN XY: 74464

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.: 13

Bravo AF: 0.00454

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00674 AC: 58

ExAC AF: 0.00601 AC: 730

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00769

EpiControl AF: 0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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

not provided Benign:4

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

Ellis-van Creveld syndrome Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 04, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
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. -

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
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	T
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

Other links and lift over

dbSNP: rs41269547; hg19: chr4-5721084;