4-5753815-C-T

Variant names:

• chr4-5753815-C-T
• rs2302075
• NM_153717.3:c.1346C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153717.3(EVC):​c.1346C>T​(p.Thr449Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,936 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. 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. T449R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.433
• Publications: 39 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055538625).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	NM_153717.3	MANE Select	c.1346C>T	p.Thr449Met	missense	Exon 10 of 21	NP_714928.1
	EVC	NM_001306090.2		c.1346C>T	p.Thr449Met	missense	Exon 10 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.1346C>T	p.Thr449Met	missense	Exon 10 of 12	NP_001293021.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	ENST00000264956.11	TSL:1 MANE Select	c.1346C>T	p.Thr449Met	missense	Exon 10 of 21	ENSP00000264956.6
	EVC	ENST00000509451.1	TSL:1	c.1346C>T	p.Thr449Met	missense	Exon 10 of 12	ENSP00000426774.1
	EVC	ENST00000861182.1		c.1346C>T	p.Thr449Met	missense	Exon 10 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251462 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000458 AC: 67 AN: 1461868 Hom.: 0 Cov.: 62 AF XY: 0.0000495 AC XY: 36 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74256

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 153211

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.43
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.027
Sift	Benign	0.047	D
Sift4G	Uncertain	0.052	T
Polyphen		0.036	B
Vest4		0.13
MutPred		0.27		Gain of stability (P = 0.0144)
MVP		0.36
ClinPred		0.036	T
GERP RS		-0.27
Varity_R		0.021
gMVP		0.045
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2302075; hg19: chr4-5755542;