4-5793685-C-T

Position:

• chr4-5793685-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.1854C>T​(p.Gly618Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 1,550,636 control chromosomes in the GnomAD database, including 87,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6782 hom., cov: 32)
  • Exomes 𝑓: 0.33 (80949 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.80

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 4-5793685-C-T is Benign according to our data. Variant chr4-5793685-C-T is described in ClinVar as [Benign]. Clinvar id is 262769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5793685-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.8 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC	NM_153717.3	c.1854C>T	p.Gly618Gly	synonymous_variant	13/21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.1854C>T	p.Gly618Gly	synonymous_variant	13/21	1	NM_153717.3	ENSP00000264956.6
EVC	ENST00000506240.1	n.172C>T		non_coding_transcript_exon_variant	1/2	3
EVC	ENST00000515113.1	n.78C>T		non_coding_transcript_exon_variant	1/4	5
CRMP1	ENST00000506216.5	n.1647+31809G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41578 AN: 151892 Hom.: 6776 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.516

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.284

GnomAD3 exomes AF: 0.355 AC: 55868 AN: 157544 Hom.: 10921 AF XY: 0.369 AC XY: 30646 AN XY: 83068

Gnomad AFR exome AF: 0.0953

Gnomad AMR exome AF: 0.345

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.514

Gnomad SAS exome AF: 0.525

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.337

GnomAD4 exome AF: 0.333 AC: 465360 AN: 1398626 Hom.: 80949 Cov.: 37 AF XY: 0.339 AC XY: 233910 AN XY: 689968

Gnomad4 AFR exome AF: 0.0979

Gnomad4 AMR exome AF: 0.341

Gnomad4 ASJ exome AF: 0.304

Gnomad4 EAS exome AF: 0.504

Gnomad4 SAS exome AF: 0.520

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.321

Gnomad4 OTH exome AF: 0.331

GnomAD4 genome AF: 0.274 AC: 41603 AN: 152010 Hom.: 6782 Cov.: 32 AF XY: 0.283 AC XY: 21037 AN XY: 74272

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.310

Gnomad4 EAS AF: 0.518

Gnomad4 SAS AF: 0.534

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.282

Alfa AF: 0.226 Hom.: 1404

Bravo AF: 0.265

Asia WGS AF: 0.481 AC: 1671 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

Ellis-van Creveld syndrome Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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 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	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

- -

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	-0.69
CADD	Benign	1.7
DANN	Benign	0.80

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: rs11737221; hg19: chr4-5795412; COSMIC: COSV53832761;