rs1553871792

Variant names:

• chr4-5741760-T-TA
• rs1553871792
• NM_153717.3:c.752dupA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_153717.3(EVC):​c.752dupA​(p.Lys252GlufsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000211 in 1,421,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EVC NM_153717.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.80

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-5741760-T-TA is Pathogenic according to our data. Variant chr4-5741760-T-TA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3	c.752dupA	p.Lys252GlufsTer4	frameshift_variant	Exon 6 of 21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.752dupA	p.Lys252GlufsTer4	frameshift_variant	Exon 6 of 21	1	NM_153717.3	ENSP00000264956.6
EVC	ENST00000509451.1	c.752dupA	p.Lys252GlufsTer4	frameshift_variant	Exon 6 of 12	1		ENSP00000426774.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1421644 Hom.: 0 Cov.: 26 AF XY: 0.00000282 AC XY: 2 AN XY: 709244

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: 0.00000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ellis-van Creveld syndrome Pathogenic:2

Feb 13, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Jun 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with Ellis-van Creveld syndrome (PMID: 23220543). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 556656). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys252Glufs*4) 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553871792; hg19: chr4-5743487;