rs2291151

chr4-5811051-G-Achr4-5811051-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153717.3(EVC):c.*14G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,600,302 control chromosomes in the GnomAD database, including 294,057 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (27977 hom., cov: 33)
  • Exomes 𝑓: 0.60 (266080 hom.)
• Consequence: EVC NM_153717.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.778

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]

CRMP1 (HGNC:2365): (collapsin response mediator protein 1) This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 4-5811051-G-A is Benign according to our data. Variant chr4-5811051-G-A is described in ClinVar as [Benign]. Clinvar id is 262759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5811051-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.*14G>A		3_prime_UTR_variant	21/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.*14G>A		3_prime_UTR_variant	21/21	1	NM_153717.3	P1
CRMP1	ENST00000506216.5	n.1647+14443C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.604 AC: 91736 AN: 151946 Hom.: 27948 Cov.: 33

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.551

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.701

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.589

GnomAD3 exomes AF: 0.579 AC: 136742 AN: 236022 Hom.: 40579 AF XY: 0.587 AC XY: 74686 AN XY: 127314

Gnomad AFR exome AF: 0.629

Gnomad AMR exome AF: 0.446

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.339

Gnomad SAS exome AF: 0.628

Gnomad FIN exome AF: 0.693

Gnomad NFE exome AF: 0.615

Gnomad OTH exome AF: 0.589

GnomAD4 exome AF: 0.603 AC: 872793 AN: 1448238 Hom.: 266080 Cov.: 30 AF XY: 0.604 AC XY: 434708 AN XY: 719906

Gnomad4 AFR exome AF: 0.628

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.603

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.629

Gnomad4 FIN exome AF: 0.682

Gnomad4 NFE exome AF: 0.612

Gnomad4 OTH exome AF: 0.596

GnomAD4 genome AF: 0.604 AC: 91810 AN: 152064 Hom.: 27977 Cov.: 33 AF XY: 0.604 AC XY: 44904 AN XY: 74296

Gnomad4 AFR AF: 0.627

Gnomad4 AMR AF: 0.531

Gnomad4 ASJ AF: 0.601

Gnomad4 EAS AF: 0.331

Gnomad4 SAS AF: 0.604

Gnomad4 FIN AF: 0.701

Gnomad4 NFE AF: 0.613

Gnomad4 OTH AF: 0.585

Alfa AF: 0.575 Hom.: 6288

Bravo AF: 0.586

Asia WGS AF: 0.484 AC: 1688 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Ellis-van Creveld syndrome Benign:2

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	- -

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	-0.94
Cadd	Benign	0.26
Dann	Benign	0.54

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: rs2291151; hg19: chr4-5812778; COSMIC: COSV53830500;