4-5752852-C-T

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.1115C>T(p.Thr372Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.086 in 1,614,038 control chromosomes in the GnomAD database, including 6,743 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T372T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.063 (449 hom., cov: 34)
  • Exomes 𝑓: 0.088 (6294 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.38

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 (MetaRNN=0.0014209151).
• BP6: Variant 4-5752852-C-T is Benign according to our data. Variant chr4-5752852-C-T is described in ClinVar as [Benign]. Clinvar id is 262765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5752852-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.1115C>T	p.Thr372Met	missense_variant	9/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.1115C>T	p.Thr372Met	missense_variant	9/21	1	NM_153717.3	P1
EVC	ENST00000509451.1	c.1115C>T	p.Thr372Met	missense_variant	9/12	1
EVC	ENST00000514919.1	n.178C>T		non_coding_transcript_exon_variant	1/2	2
CRMP1	ENST00000506216.5	n.1648-4540G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 9600 AN: 152190 Hom.: 450 Cov.: 34

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0400

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0927

Gnomad OTH AF: 0.0521

GnomAD3 exomes AF: 0.0673 AC: 16901 AN: 251260 Hom.: 779 AF XY: 0.0691 AC XY: 9382 AN XY: 135854

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.0276

Gnomad ASJ exome AF: 0.0783

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0419

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0930

Gnomad OTH exome AF: 0.0694

GnomAD4 exome AF: 0.0884 AC: 129174 AN: 1461730 Hom.: 6294 Cov.: 35 AF XY: 0.0872 AC XY: 63411 AN XY: 727166

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.0282

Gnomad4 ASJ exome AF: 0.0796

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0421

Gnomad4 FIN exome AF: 0.120

Gnomad4 NFE exome AF: 0.0992

Gnomad4 OTH exome AF: 0.0772

GnomAD4 genome AF: 0.0630 AC: 9601 AN: 152308 Hom.: 449 Cov.: 34 AF XY: 0.0630 AC XY: 4688 AN XY: 74464

Gnomad4 AFR AF: 0.0167

Gnomad4 AMR AF: 0.0351

Gnomad4 ASJ AF: 0.0801

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0400

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.0926

Gnomad4 OTH AF: 0.0530

Alfa AF: 0.0861 Hom.: 772

Bravo AF: 0.0548

TwinsUK AF: 0.0992 AC: 368

ALSPAC AF: 0.107 AC: 412

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.0898 AC: 772

ExAC AF: 0.0674 AC: 8178

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Pars Genome Lab	Jun 15, 2021	- -
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 26, 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

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.76	T;D
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.060
Sift	Benign	0.22	T;T
Sift4G	Benign	0.36	T;D
Polyphen		0.97	D;.
Vest4		0.13
ClinPred		0.016	T
GERP RS		3.8
Varity_R		0.049
gMVP		0.17

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: rs28483498; hg19: chr4-5754579;