rs111293777

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_153717.3(EVC):c.1855G>A(p.Val619Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000795 in 1,551,356 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V619V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0033 ( 5 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 7 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.47

Variant links:

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 links:

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]

CRMP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008758903).

BP6

Variant 4-5793686-G-A is Benign according to our data. Variant chr4-5793686-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 194283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3 linkuse as main transcript	c.1855G>A	p.Val619Ile	missense_variant	13/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
EVC	ENST00000264956.11 linkuse as main transcript	c.1855G>A	p.Val619Ile	missense_variant	13/21	1	NM_153717.3	P1
EVC	ENST00000506240.1 linkuse as main transcript	n.173G>A		non_coding_transcript_exon_variant	1/2	3
EVC	ENST00000515113.1 linkuse as main transcript	n.79G>A		non_coding_transcript_exon_variant	1/4	5
CRMP1	ENST00000506216.5 linkuse as main transcript	n.1647+31808C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00325

AC:

494

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00117

AC:

185

AN:

157494

Hom.:

AF XY:

0.00113

AC XY:

AN XY:

83070

show subpopulations

Gnomad AFR exome

AF:

0.0138

Gnomad AMR exome

AF:

0.000563

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000873

Gnomad SAS exome

AF:

0.00188

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000656

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000526

AC:

736

AN:

1399046

Hom.:

Cov.:

AF XY:

0.000554

AC XY:

382

AN XY:

690130

show subpopulations

Gnomad4 AFR exome

AF:

0.0153

Gnomad4 AMR exome

AF:

0.000502

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00199

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000176

Gnomad4 OTH exome

AF:

0.000898

GnomAD4 genome

AF:

0.00327

AC:

498

AN:

152310

Hom.:

Cov.:

AF XY:

0.00338

AC XY:

252

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0111

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000700

Hom.:

Bravo

AF:

0.00382

ESP6500AA

AF:

0.0106

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.00104

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ellis-van Creveld syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 16, 2019	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2019	- -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.63

MetaRNN

Benign

0.0088

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.60

REVEL

Benign

0.12

Sift

Benign

0.033

Sift4G

Uncertain

0.035

Polyphen

0.99

Vest4

0.33

MVP

0.54

ClinPred

0.022

GERP RS

5.2

Varity_R

0.094

gMVP

0.078

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over