4-5752817-T-C

Position:

• chr4-5752817-T-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.1099-19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,612,372 control chromosomes in the GnomAD database, including 148,019 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11572 hom., cov: 33)
  • Exomes 𝑓: 0.43 (136447 hom.)
• Consequence: EVC NM_153717.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.802

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=-0.88).
• BP6: Variant 4-5752817-T-C is Benign according to our data. Variant chr4-5752817-T-C is described in ClinVar as [Benign]. Clinvar id is 262764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5752817-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVC	NM_153717.3	c.1099-19T>C		intron_variant		ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.1099-19T>C		intron_variant		1	NM_153717.3	ENSP00000264956	P1
EVC	ENST00000509451.1	c.1099-19T>C		intron_variant		1		ENSP00000426774
EVC	ENST00000514919.1	n.143T>C		non_coding_transcript_exon_variant	1/2	2
CRMP1	ENST00000506216.5	n.1648-4505A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56686 AN: 152032 Hom.: 11576 Cov.: 33

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.376

GnomAD3 exomes AF: 0.408 AC: 102352 AN: 250600 Hom.: 21919 AF XY: 0.404 AC XY: 54848 AN XY: 135598

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.481

Gnomad ASJ exome AF: 0.475

Gnomad EAS exome AF: 0.313

Gnomad SAS exome AF: 0.287

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.450

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.427 AC: 623859 AN: 1460222 Hom.: 136447 Cov.: 35 AF XY: 0.423 AC XY: 307433 AN XY: 726546

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.480

Gnomad4 ASJ exome AF: 0.482

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.443

Gnomad4 NFE exome AF: 0.446

Gnomad4 OTH exome AF: 0.415

GnomAD4 genome AF: 0.373 AC: 56699 AN: 152150 Hom.: 11572 Cov.: 33 AF XY: 0.369 AC XY: 27474 AN XY: 74356

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.481

Gnomad4 EAS AF: 0.315

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.439

Gnomad4 NFE AF: 0.448

Gnomad4 OTH AF: 0.375

Alfa AF: 0.439 Hom.: 16228

Bravo AF: 0.369

Asia WGS AF: 0.273 AC: 950 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 08, 2015	- -

Ellis-van Creveld syndrome Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

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	-0.88
CADD	Benign	0.14
DANN	Benign	0.60

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: rs899691; hg19: chr4-5754544; COSMIC: COSV53829052;