4-5753839-AG-A

Variant names:

• chr4-5753839-AG-A
• rs760607210
• NM_153717.3:c.1373delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_153717.3(EVC):​c.1373delG​(p.Gly458GlufsTer42) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EVC NM_153717.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.540
• Publications: 0 publications found

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]

CRMP1 (HGNC:2365): (collapsin response mediator protein 1) This gene encodes a member of a family of cytosolic phosphoproteins expressed exclusively in the nervous system. The encoded protein is thought to be a part of the semaphorin signal transduction pathway implicated in semaphorin-induced growth cone collapse during neural development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 4-5753839-AG-A is Pathogenic according to our data. Variant chr4-5753839-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 555852.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153717.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	NM_153717.3	MANE Select	c.1373delG	p.Gly458GlufsTer42	frameshift	Exon 10 of 21	NP_714928.1
	EVC	NM_001306090.2		c.1373delG	p.Gly458GlufsTer42	frameshift	Exon 10 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.1373delG	p.Gly458GlufsTer42	frameshift	Exon 10 of 12	NP_001293021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	ENST00000264956.11	TSL:1 MANE Select	c.1373delG	p.Gly458GlufsTer42	frameshift	Exon 10 of 21	ENSP00000264956.6
	EVC	ENST00000509451.1	TSL:1	c.1373delG	p.Gly458GlufsTer42	frameshift	Exon 10 of 12	ENSP00000426774.1
	EVC	ENST00000514919.1	TSL:2	n.436delG		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251472 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly458Glufs*42) 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). This variant is present in population databases (rs760607210, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with EVC-related conditions (PMID: 23220543). ClinVar contains an entry for this variant (Variation ID: 555852). For these reasons, this variant has been classified as Pathogenic.

Ellis-van Creveld syndrome Pathogenic:1

Dec 29, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs760607210; hg19: chr4-5755566;