dbSNP rs1553857801: EVC:p.Met1? (chr4-5711382-T-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_153717.3(EVC):c.2T>A(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

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -0.115

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 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 92 codons. Genomic position: 5719347. Lost 0.092 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-5711382-T-A is Pathogenic according to our data. Variant chr4-5711382-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-5711382-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 21	ENST00000264956.11	NP_714928.1	P57679

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 21	1	NM_153717.3	ENSP00000264956.6		P57679
EVC	ENST00000509451.1 link	c.2T>A	p.Met1?	start_lost	Exon 1 of 12	1		ENSP00000426774.1		E9PCN4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

861606

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

401750

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: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ellis-van Creveld syndrome

Pathogenic:2

Apr 24, 2018

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Dec 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 558005). 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. This sequence change affects the initiator methionine of the EVC mRNA. The next in-frame methionine is located at codon 92. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.062

T;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-1.0

PROVEAN

Benign

-0.38

N;N

REVEL

Benign

0.21

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.038

B;.

Vest4

0.73

MutPred

1.0

Loss of stability (P = 0.0331);Loss of stability (P = 0.0331);

MVP

0.53

ClinPred

0.62

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.71

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