rs121908426

Positions:

chr4-5745321-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_153717.3(EVC):c.919T>C(p.Ser307Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S307C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

EVC
NM_153717.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 0.0660

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_153717.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

PP5

Variant 4-5745321-T-C is Pathogenic according to our data. Variant chr4-5745321-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5745321-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3 linkuse as main transcript	c.919T>C	p.Ser307Pro	missense_variant	7/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11 linkuse as main transcript	c.919T>C	p.Ser307Pro	missense_variant	7/21	1	NM_153717.3	P1
EVC	ENST00000509451.1 linkuse as main transcript	c.919T>C	p.Ser307Pro	missense_variant	7/12	1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251472

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ellis-van Creveld syndrome

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 09, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 05, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 12, 2021	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 307 of the EVC protein (p.Ser307Pro). This variant is present in population databases (rs121908426, gnomAD 0.01%). This missense change has been observed in individual(s) with EVC-related conditions (PMID: 10700184, 29321360). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EVC protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.84

T;D

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Benign

-0.49

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

0.0000072

A;A;A

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.3

N;D

REVEL

Uncertain

0.37

Sift

Benign

0.16

T;T

Sift4G

Uncertain

0.012

D;D

Polyphen

1.0

D;.

Vest4

0.70

MutPred

0.67

Gain of glycosylation at S307 (P = 0.0135);Gain of glycosylation at S307 (P = 0.0135);

MVP

0.64

ClinPred

0.42

GERP RS

-0.53

Varity_R

0.29

gMVP

0.63

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