4-5748306-G-C

Variant names:

• chr4-5748306-G-C
• rs762531567
• NM_153717.3:c.1098G>C
• EVC p.Leu366Leu

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_153717.3(EVC):​c.1098G>C​(p.Leu366Leu) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L366L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EVC NM_153717.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.76
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1098G>C	p.Leu366Leu	splice_region synonymous	Exon 8 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.1098G>C	p.Leu366Leu	splice_region synonymous	Exon 8 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.1098G>C	p.Leu366Leu	splice_region synonymous	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.1098G>C	p.Leu366Leu	splice_region synonymous	Exon 8 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.1098G>C	p.Leu366Leu	splice_region synonymous	Exon 8 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.1098G>C	p.Leu366Leu	splice_region synonymous	Exon 8 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Benign	0.88
PhyloP100		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.70		Position offset: 0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs762531567; hg19: chr4-5750033;