4-5741782-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153717.3(EVC):c.769C>T(p.Leu257=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.941 in 1,552,778 control chromosomes in the GnomAD database, including 687,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L257L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.96 (69532 hom., cov: 33)
  • Exomes 𝑓: 0.94 (617958 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.00

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-5741782-C-T is Benign according to our data. Variant chr4-5741782-C-T is described in ClinVar as [Benign]. Clinvar id is 198281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5741782-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.769C>T	p.Leu257=	synonymous_variant	6/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.769C>T	p.Leu257=	synonymous_variant	6/21	1	NM_153717.3	P1
EVC	ENST00000509451.1	c.769C>T	p.Leu257=	synonymous_variant	6/12	1

Frequencies

GnomAD3 genomes AF: 0.955 AC: 145268 AN: 152090 Hom.: 69466 Cov.: 33

Gnomad AFR AF: 0.989

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.968

Gnomad ASJ AF: 0.931

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.911

Gnomad FIN AF: 0.959

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.954

GnomAD3 exomes AF: 0.948 AC: 237096 AN: 250044 Hom.: 112540 AF XY: 0.944 AC XY: 127730 AN XY: 135256

Gnomad AFR exome AF: 0.991

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.936

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.906

Gnomad FIN exome AF: 0.954

Gnomad NFE exome AF: 0.935

Gnomad OTH exome AF: 0.943

GnomAD4 exome AF: 0.939 AC: 1314994 AN: 1400570 Hom.: 617958 Cov.: 26 AF XY: 0.937 AC XY: 656225 AN XY: 700004

Gnomad4 AFR exome AF: 0.991

Gnomad4 AMR exome AF: 0.981

Gnomad4 ASJ exome AF: 0.933

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.908

Gnomad4 FIN exome AF: 0.954

Gnomad4 NFE exome AF: 0.935

Gnomad4 OTH exome AF: 0.943

GnomAD4 genome AF: 0.955 AC: 145394 AN: 152208 Hom.: 69532 Cov.: 33 AF XY: 0.956 AC XY: 71132 AN XY: 74408

Gnomad4 AFR AF: 0.990

Gnomad4 AMR AF: 0.968

Gnomad4 ASJ AF: 0.931

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.912

Gnomad4 FIN AF: 0.959

Gnomad4 NFE AF: 0.932

Gnomad4 OTH AF: 0.954

Alfa AF: 0.939 Hom.: 101228

Bravo AF: 0.960

Asia WGS AF: 0.957 AC: 3321 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Ellis-van Creveld syndrome Benign:4

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	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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
BayesDel_noAF	Benign	-0.77
Cadd	Benign	4.8
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs6446393; hg19: chr4-5743509;