chr4-5748207-G-GAACATTC

Variant names:

• chr4-5748207-G-GAACATTC
• NM_153717.3:c.999_1000insAACATTC

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.999_1000insAACATTC​(p.Cys334AsnfsTer52) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EVC NM_153717.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.61
• 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 4-5748207-G-GAACATTC is Pathogenic according to our data. Variant chr4-5748207-G-GAACATTC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1724683.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	NM_153717.3	MANE Select	c.999_1000insAACATTC	p.Cys334AsnfsTer52	frameshift	Exon 8 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.999_1000insAACATTC	p.Cys334AsnfsTer52	frameshift	Exon 8 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.999_1000insAACATTC	p.Cys334AsnfsTer52	frameshift	Exon 8 of 12	NP_001293021.1	E9PCN4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	ENST00000264956.11	TSL:1 MANE Select	c.999_1000insAACATTC	p.Cys334AsnfsTer52	frameshift	Exon 8 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.999_1000insAACATTC	p.Cys334AsnfsTer52	frameshift	Exon 8 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.999_1000insAACATTC	p.Cys334AsnfsTer52	frameshift	Exon 8 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Ellis-van Creveld syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6

Splicing

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

Other links and lift over

hg19: chr4-5749934;