rs35870680

Positions:

• chr4-5719322-A-G

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.249A>G​(p.Ser83Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,614,116 control chromosomes in the GnomAD database, including 15,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1001 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14095 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.08

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=-0.92).
• BP6: Variant 4-5719322-A-G is Benign according to our data. Variant chr4-5719322-A-G is described in ClinVar as [Benign]. Clinvar id is 262776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC	NM_153717.3	c.249A>G	p.Ser83Ser	synonymous_variant	2/21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.249A>G	p.Ser83Ser	synonymous_variant	2/21	1	NM_153717.3	ENSP00000264956.6
EVC	ENST00000509451.1	c.249A>G	p.Ser83Ser	synonymous_variant	2/12	1		ENSP00000426774.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15330 AN: 152152 Hom.: 1001 Cov.: 32

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0842

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.115 AC: 29015 AN: 251472 Hom.: 2017 AF XY: 0.122 AC XY: 16537 AN XY: 135908

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.0633

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.128

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.134 AC: 195561 AN: 1461846 Hom.: 14095 Cov.: 34 AF XY: 0.135 AC XY: 98343 AN XY: 727228

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.0690

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.101 AC: 15327 AN: 152270 Hom.: 1001 Cov.: 32 AF XY: 0.0981 AC XY: 7303 AN XY: 74456

Gnomad4 AFR AF: 0.0264

Gnomad4 AMR AF: 0.0840

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.145

Gnomad4 OTH AF: 0.118

Alfa AF: 0.134 Hom.: 772

Bravo AF: 0.0939

Asia WGS AF: 0.0540 AC: 186 AN: 3478

EpiCase AF: 0.162

EpiControl AF: 0.163

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ellis-van Creveld syndrome Benign:3

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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 14, 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. -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.40
DANN	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs35870680; hg19: chr4-5721049; COSMIC: COSV53832739;