4-5783715-G-T

Variant names:

• chr4-5783715-G-T
• rs1383180
• NM_153717.3:c.1727G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_153717.3(EVC):​c.1727G>T​(p.Arg576Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R576Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.16
• Publications: 38 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

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.1727G>T	p.Arg576Leu	missense	Exon 12 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.1727G>T	p.Arg576Leu	missense	Exon 12 of 21	NP_001293019.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	ENST00000264956.11	TSL:1 MANE Select	c.1727G>T	p.Arg576Leu	missense	Exon 12 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000861182.1		c.1727G>T	p.Arg576Leu	missense	Exon 12 of 21	ENSP00000531241.1
	EVC	ENST00000960562.1		c.1589G>T	p.Arg530Leu	missense	Exon 11 of 20	ENSP00000630621.1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 250448 AF XY: 0.0000222

Gnomad AFR exome AF: 0.000371

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461530 Hom.: 0 Cov.: 54 AF XY: 0.00000688 AC XY: 5 AN XY: 727052

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111792

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152020 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74244

African (AFR) AF: 0.000242 AC: 10 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 47524

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.2
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.23
Sift	Benign	0.083	T
Sift4G	Benign	0.068	T
Polyphen		1.0	D
Vest4		0.69
MutPred		0.31		Loss of loop (P = 0.0153)
MVP		0.76
ClinPred		0.86	D
GERP RS		4.1
Varity_R		0.22
gMVP		0.46
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1383180; hg19: chr4-5785442;