4-5711382-T-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.115

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_153717.3 (EVC) was described as [Pathogenic] in ClinVar as 2936900
• 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/exons	MANE	UniProt
EVC	NM_153717.3	c.2T>A	p.Met1?	start_lost	1/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.2T>A	p.Met1?	start_lost	1/21	1	NM_153717.3	P1
EVC	ENST00000509451.1	c.2T>A	p.Met1?	start_lost	1/12	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 861606 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ellis-van Creveld syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Apr 24, 2018

- -

Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 03, 2021

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 variant is not present in population databases (gnomAD no frequency). 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	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
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	D
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

Other links and lift over

dbSNP: rs1553857801; hg19: chr4-5713109;