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4-5711405-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_153717.3(EVC):c.25A>T(p.Lys9Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000229 in 872,936 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K9K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

EVC
NM_153717.3 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.289
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 142 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-5711405-A-T is Pathogenic according to our data. Variant chr4-5711405-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1452180.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EVCNM_153717.3 linkuse as main transcriptc.25A>T p.Lys9Ter stop_gained 1/21 ENST00000264956.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EVCENST00000264956.11 linkuse as main transcriptc.25A>T p.Lys9Ter stop_gained 1/211 NM_153717.3 P1
EVCENST00000509451.1 linkuse as main transcriptc.25A>T p.Lys9Ter stop_gained 1/121

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000229
AC:
2
AN:
872936
Hom.:
0
Cov.:
29
AF XY:
0.00000245
AC XY:
1
AN XY:
408896
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:
0.0000561
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000127
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: 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
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 13, 2020For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with EVC-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change creates a premature translational stop signal (p.Lys9*) in the EVC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EVC are known to be pathogenic (PMID: 23220543). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.27
Cadd
Pathogenic
35
Dann
Uncertain
0.99
Eigen
Benign
-0.13
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.023
N
MutationTaster
Benign
1.0
A;A;A
Vest4
0.39
GERP RS
0.85
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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.

Other links and lift over

hg19: chr4-5713132; API