chr4-5756299-G-A

Variant names:

• chr4-5756299-G-A
• rs149898884
• NM_153717.3:c.1500G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_153717.3(EVC):​c.1500G>A​(p.Met500Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,613,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:3
• Conservation: PhyloP100: -0.454
• Publications: 4 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_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055836737).
• BP6: Variant 4-5756299-G-A is Benign according to our data. Variant chr4-5756299-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446659.

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.1500G>A	p.Met500Ile	missense	Exon 11 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.1500G>A	p.Met500Ile	missense	Exon 11 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.1500G>A	p.Met500Ile	missense	Exon 11 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.1500G>A	p.Met500Ile	missense	Exon 11 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.1500G>A	p.Met500Ile	missense	Exon 11 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.1500G>A	p.Met500Ile	missense	Exon 11 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000390 AC: 97 AN: 248410 AF XY: 0.000343

Gnomad AFR exome AF: 0.00541

Gnomad AMR exome AF: 0.000233

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: 0.000331

GnomAD4 exome AF: 0.000189 AC: 276 AN: 1460876 Hom.: 0 Cov.: 32 AF XY: 0.000173 AC XY: 126 AN XY: 726548

African (AFR) AF: 0.00666 AC: 223 AN: 33468

American (AMR) AF: 0.000246 AC: 11 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111794

Other (OTH) AF: 0.000298 AC: 18 AN: 60352

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00159 AC XY: 118 AN XY: 74440

African (AFR) AF: 0.00520 AC: 216 AN: 41554

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000613 Hom.: 1

Bravo AF: 0.00191

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000544 AC: 66

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	1	Ellis-van Creveld syndrome (4)
-	1	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (2)
-	-	1	EVC-related disorder (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.094
DANN	Benign	0.59
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.45
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.055
Sift	Benign	0.27	T
Sift4G	Benign	0.55	T
Polyphen		0.0030	B
Vest4		0.22
MutPred		0.28		Loss of loop (P = 0.0073)
MVP		0.055
ClinPred		0.017	T
GERP RS		-6.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.069
Mutation Taster		=28/72	disease causing

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: rs149898884; hg19: chr4-5758026;