rs141859946

chr4-5753838-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_153717.3(EVC):c.1369G>A(p.Glu457Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,614,114 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 2.55

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052634776).
• BP6: Variant 4-5753838-G-A is Benign according to our data. Variant chr4-5753838-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 349176.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=5, Uncertain_significance=1}. Variant chr4-5753838-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.1369G>A	p.Glu457Lys	missense_variant	10/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.1369G>A	p.Glu457Lys	missense_variant	10/21	1	NM_153717.3	P1
EVC	ENST00000509451.1	c.1369G>A	p.Glu457Lys	missense_variant	10/12	1
EVC	ENST00000514919.1	n.432G>A		non_coding_transcript_exon_variant	2/2	2
CRMP1	ENST00000506216.5	n.1648-5526C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 292 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00208 AC: 522 AN: 251470 Hom.: 1 AF XY: 0.00214 AC XY: 291 AN XY: 135910

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00289

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00272 AC: 3970 AN: 1461820 Hom.: 8 Cov.: 35 AF XY: 0.00269 AC XY: 1956 AN XY: 727206

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00727

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000928

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00298

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.00183 AC XY: 136 AN XY: 74472

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00293 Hom.: 1

Bravo AF: 0.00204

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00213 AC: 259

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	EVC: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Ellis-van Creveld syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 17, 2017

- -

EVC-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.076	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.022	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.040
Sift	Benign	0.71	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.12	B;.
Vest4		0.23
MVP		0.48
ClinPred		0.017	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.093

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141859946; hg19: chr4-5755565;