Variant 4-5711381-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_153717.3(EVC):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EVC
NM_153717.3 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.74

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.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_153717.3 (EVC) was described as [Likely_pathogenic] in ClinVar as 558005

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-5711381-A-G is Pathogenic according to our data. Variant chr4-5711381-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2123597.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/21	1	NM_153717.3	P1
EVC	ENST00000509451.1 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	1/12	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

861424

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

401648

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2022

This sequence change affects the initiator methionine of the EVC mRNA. The next in-frame methionine is located at codon 92. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with Ellis-van Creveld syndrome (PMID: 19810119, 28854412). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

0.0092

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.094

T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

D;D;D

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.22

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.017

B;.

Vest4

0.79

MutPred

1.0

Loss of MoRF binding (P = 0.1026);Loss of MoRF binding (P = 0.1026);

MVP

0.26

ClinPred

0.51

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.92

gMVP

0.54

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over