4-5753815-C-A

Position:

• chr4-5753815-C-A

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.1346C>A​(p.Thr449Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 1,613,976 control chromosomes in the GnomAD database, including 518,043 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (53273 hom., cov: 32)
  • Exomes 𝑓: 0.80 (464770 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.433

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.731524E-7).
• BP6: Variant 4-5753815-C-A is Benign according to our data. Variant chr4-5753815-C-A is described in ClinVar as [Benign]. Clinvar id is 167044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5753815-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC	NM_153717.3	c.1346C>A	p.Thr449Lys	missense_variant	10/21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.1346C>A	p.Thr449Lys	missense_variant	10/21	1	NM_153717.3	ENSP00000264956.6
EVC	ENST00000509451.1	c.1346C>A	p.Thr449Lys	missense_variant	10/12	1		ENSP00000426774.1
EVC	ENST00000514919.1	n.409C>A		non_coding_transcript_exon_variant	2/2	2
CRMP1	ENST00000506216.5	n.1648-5503G>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.833 AC: 126668 AN: 152046 Hom.: 53221 Cov.: 32

Gnomad AFR AF: 0.956

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.832

Gnomad EAS AF: 0.819

Gnomad SAS AF: 0.776

Gnomad FIN AF: 0.772

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.788

Gnomad OTH AF: 0.822

GnomAD3 exomes AF: 0.791 AC: 198863 AN: 251462 Hom.: 79004 AF XY: 0.789 AC XY: 107203 AN XY: 135902

Gnomad AFR exome AF: 0.961

Gnomad AMR exome AF: 0.713

Gnomad ASJ exome AF: 0.827

Gnomad EAS exome AF: 0.812

Gnomad SAS exome AF: 0.779

Gnomad FIN exome AF: 0.768

Gnomad NFE exome AF: 0.791

Gnomad OTH exome AF: 0.784

GnomAD4 exome AF: 0.797 AC: 1164596 AN: 1461812 Hom.: 464770 Cov.: 62 AF XY: 0.795 AC XY: 578466 AN XY: 727214

Gnomad4 AFR exome AF: 0.961

Gnomad4 AMR exome AF: 0.720

Gnomad4 ASJ exome AF: 0.831

Gnomad4 EAS exome AF: 0.814

Gnomad4 SAS exome AF: 0.781

Gnomad4 FIN exome AF: 0.763

Gnomad4 NFE exome AF: 0.796

Gnomad4 OTH exome AF: 0.807

GnomAD4 genome AF: 0.833 AC: 126777 AN: 152164 Hom.: 53273 Cov.: 32 AF XY: 0.829 AC XY: 61676 AN XY: 74376

Gnomad4 AFR AF: 0.956

Gnomad4 AMR AF: 0.770

Gnomad4 ASJ AF: 0.832

Gnomad4 EAS AF: 0.819

Gnomad4 SAS AF: 0.778

Gnomad4 FIN AF: 0.772

Gnomad4 NFE AF: 0.788

Gnomad4 OTH AF: 0.824

Alfa AF: 0.796 Hom.: 109652

Bravo AF: 0.839

TwinsUK AF: 0.809 AC: 2999

ALSPAC AF: 0.809 AC: 3119

ESP6500AA AF: 0.954 AC: 4203

ESP6500EA AF: 0.801 AC: 6886

ExAC AF: 0.796 AC: 96695

Asia WGS AF: 0.789 AC: 2746 AN: 3478

EpiCase AF: 0.794

EpiControl AF: 0.795

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2014	- -
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, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Ellis-van Creveld syndrome Benign:4

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	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

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

-

- -

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
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.44
DANN	Benign	0.81
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.038	T;T
MetaRNN	Benign	5.7e-7	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.8	N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.9	N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.062
ClinPred		0.0016	T
GERP RS		-0.27
Varity_R		0.035
gMVP		0.047

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: rs2302075; hg19: chr4-5755542;