rs28483498

Variant names:

• chr4-5752852-C-T
• rs28483498
• NM_153717.3:c.1115C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-5752852-C-T
• chr4-5752852-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153717.3(EVC):​c.1115C>T​(p.Thr372Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.086 in 1,614,038 control chromosomes in the GnomAD database, including 6,743 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T372T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.063 (449 hom., cov: 34)
  • Exomes 𝑓: 0.088 (6294 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.38
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014209151).
• BP6: Variant 4-5752852-C-T is Benign according to our data. Variant chr4-5752852-C-T is described in ClinVar as Benign. ClinVar VariationId is 262765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0907 is higher than 0.05.

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.1115C>T	p.Thr372Met	missense	Exon 9 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.1115C>T	p.Thr372Met	missense	Exon 9 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.1115C>T	p.Thr372Met	missense	Exon 9 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.1115C>T	p.Thr372Met	missense	Exon 9 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.1115C>T	p.Thr372Met	missense	Exon 9 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.1115C>T	p.Thr372Met	missense	Exon 9 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 9600 AN: 152190 Hom.: 450 Cov.: 34

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0400

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0927

Gnomad OTH AF: 0.0521

GnomAD2 exomes AF: 0.0673 AC: 16901 AN: 251260 AF XY: 0.0691

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.0276

Gnomad ASJ exome AF: 0.0783

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0930

Gnomad OTH exome AF: 0.0694

GnomAD4 exome AF: 0.0884 AC: 129174 AN: 1461730 Hom.: 6294 Cov.: 35 AF XY: 0.0872 AC XY: 63411 AN XY: 727166

African (AFR) AF: 0.0155 AC: 519 AN: 33480

American (AMR) AF: 0.0282 AC: 1262 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0796 AC: 2080 AN: 26136

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39698

South Asian (SAS) AF: 0.0421 AC: 3629 AN: 86258

European-Finnish (FIN) AF: 0.120 AC: 6423 AN: 53414

Middle Eastern (MID) AF: 0.0437 AC: 252 AN: 5768

European-Non Finnish (NFE) AF: 0.0992 AC: 110333 AN: 1111858

Other (OTH) AF: 0.0772 AC: 4663 AN: 60394

GnomAD4 genome AF: 0.0630 AC: 9601 AN: 152308 Hom.: 449 Cov.: 34 AF XY: 0.0630 AC XY: 4688 AN XY: 74464

African (AFR) AF: 0.0167 AC: 694 AN: 41574

American (AMR) AF: 0.0351 AC: 538 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 278 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0400 AC: 193 AN: 4824

European-Finnish (FIN) AF: 0.127 AC: 1352 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0926 AC: 6301 AN: 68012

Other (OTH) AF: 0.0530 AC: 112 AN: 2114

Alfa AF: 0.0817 Hom.: 1034

Bravo AF: 0.0548

TwinsUK AF: 0.0992 AC: 368

ALSPAC AF: 0.107 AC: 412

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.0898 AC: 772

ExAC AF: 0.0674 AC: 8178

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ellis-van Creveld syndrome (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.4
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.060
Sift	Benign	0.22	T
Sift4G	Benign	0.36	T
Polyphen		0.97	D
Vest4		0.13
ClinPred		0.016	T
GERP RS		3.8
Varity_R		0.049
gMVP		0.17
Mutation Taster		=99/1	polymorphism (auto)

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: rs28483498; hg19: chr4-5754579; COSMIC: COSV107299064;