4-5741793-G-A

Position:

• chr4-5741793-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_153717.3(EVC):​c.780G>A​(p.Lys260=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00862 in 1,519,022 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0089 (86 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.525

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 4-5741793-G-A is Benign according to our data. Variant chr4-5741793-G-A is described in ClinVar as [Benign]. Clinvar id is 198283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.525 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC	NM_153717.3	c.780G>A	p.Lys260=	synonymous_variant	6/21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.780G>A	p.Lys260=	synonymous_variant	6/21	1	NM_153717.3	ENSP00000264956	P1
EVC	ENST00000509451.1	c.780G>A	p.Lys260=	synonymous_variant	6/12	1		ENSP00000426774

Frequencies

GnomAD3 genomes AF: 0.00655 AC: 996 AN: 152086 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00925

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00777 AC: 1940 AN: 249674 Hom.: 13 AF XY: 0.00772 AC XY: 1043 AN XY: 135148

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.00660

GnomAD4 exome AF: 0.00885 AC: 12102 AN: 1366818 Hom.: 86 Cov.: 23 AF XY: 0.00860 AC XY: 5890 AN XY: 685054

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00180

Gnomad4 ASJ exome AF: 0.00263

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000239

Gnomad4 FIN exome AF: 0.00903

Gnomad4 NFE exome AF: 0.0107

Gnomad4 OTH exome AF: 0.00658

GnomAD4 genome AF: 0.00654 AC: 995 AN: 152204 Hom.: 4 Cov.: 33 AF XY: 0.00637 AC XY: 474 AN XY: 74418

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00925

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00899 Hom.: 3

Bravo AF: 0.00592

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00871

EpiControl AF: 0.00961

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2014	- -

Ellis-van Creveld syndrome Benign:2

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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 14, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.6
DANN	Benign	0.59

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: rs41269555; hg19: chr4-5743520;