4-5752993-AGG-A

Variant names:

• chr4-5752993-AGG-A
• rs1483120703
• NM_153717.3:c.1257_1258delGG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_153717.3(EVC):​c.1257_1258delGG​(p.Glu420AlafsTer56) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000151 in 1,461,012 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: EVC NM_153717.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.04

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

Verdict is Pathogenic. Variant got 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVC	NM_153717.3	c.1257_1258delGG	p.Glu420AlafsTer56	frameshift_variant	Exon 9 of 21	ENST00000264956.11	NP_714928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVC	ENST00000264956.11	c.1257_1258delGG	p.Glu420AlafsTer56	frameshift_variant	Exon 9 of 21	1	NM_153717.3	ENSP00000264956.6
EVC	ENST00000509451.1	c.1257_1258delGG	p.Glu420AlafsTer56	frameshift_variant	Exon 9 of 12	1		ENSP00000426774.1
EVC	ENST00000514919.1	n.320_321delGG		non_coding_transcript_exon_variant	Exon 1 of 2	2
CRMP1	ENST00000506216.5	n.1648-4683_1648-4682delCC		intron_variant	Intron 12 of 12	5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461012 Hom.: 0 AF XY: 0.0000124 AC XY: 9 AN XY: 726820

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: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1483120703; hg19: chr4-5754720;