4-5748268-G-C

Position:

• chr4-5748268-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_153717.3(EVC):​c.1060G>C​(p.Glu354Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E354K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.76

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.1060G>C	p.Glu354Gln	missense_variant	8/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.1060G>C	p.Glu354Gln	missense_variant	8/21	1	NM_153717.3	P1
EVC	ENST00000509451.1	c.1060G>C	p.Glu354Gln	missense_variant	8/12	1
CRMP1	ENST00000506216.5	n.1692C>G		non_coding_transcript_exon_variant	13/13	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.098	T;T
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.46		Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.84
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.23
gMVP		0.54

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: rs779915989; hg19: chr4-5749995;