chr4-5753789-T-A

Variant names:

• chr4-5753789-T-A
• rs60582583
• NM_153717.3:c.1320T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153717.3(EVC):​c.1320T>A​(p.Phe440Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00888 in 1,614,164 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (13 hom., cov: 34)
  • Exomes 𝑓: 0.0090 (145 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.635
• Publications: 11 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=0.001494199).
• BP6: Variant 4-5753789-T-A is Benign according to our data. Variant chr4-5753789-T-A is described in ClinVar as Benign. ClinVar VariationId is 167043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00773 (1177/152296) while in subpopulation EAS AF = 0.0492 (254/5160). AF 95% confidence interval is 0.0443. There are 13 homozygotes in GnomAd4. There are 581 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AD,Unknown,AR gene

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.1320T>A	p.Phe440Leu	missense	Exon 10 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.1320T>A	p.Phe440Leu	missense	Exon 10 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.1320T>A	p.Phe440Leu	missense	Exon 10 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.1320T>A	p.Phe440Leu	missense	Exon 10 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.1320T>A	p.Phe440Leu	missense	Exon 10 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.1320T>A	p.Phe440Leu	missense	Exon 10 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.00773 AC: 1176 AN: 152178 Hom.: 13 Cov.: 34

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0491

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00679

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.0146 AC: 3661 AN: 251462 AF XY: 0.0126

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.0440

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.0584

Gnomad FIN exome AF: 0.00508

Gnomad NFE exome AF: 0.00622

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00899 AC: 13149 AN: 1461868 Hom.: 145 Cov.: 30 AF XY: 0.00853 AC XY: 6204 AN XY: 727238

African (AFR) AF: 0.00158 AC: 53 AN: 33480

American (AMR) AF: 0.0397 AC: 1774 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00536 AC: 140 AN: 26136

East Asian (EAS) AF: 0.0487 AC: 1934 AN: 39698

South Asian (SAS) AF: 0.00282 AC: 243 AN: 86256

European-Finnish (FIN) AF: 0.00490 AC: 262 AN: 53416

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5764

European-Non Finnish (NFE) AF: 0.00730 AC: 8118 AN: 1111998

Other (OTH) AF: 0.00982 AC: 593 AN: 60396

GnomAD4 genome AF: 0.00773 AC: 1177 AN: 152296 Hom.: 13 Cov.: 34 AF XY: 0.00780 AC XY: 581 AN XY: 74474

African (AFR) AF: 0.00274 AC: 114 AN: 41572

American (AMR) AF: 0.0154 AC: 235 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.0492 AC: 254 AN: 5160

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.00584 AC: 62 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00679 AC: 462 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00798 Hom.: 7

Bravo AF: 0.0100

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.0127 AC: 1544

Asia WGS AF: 0.0250 AC: 87 AN: 3478

EpiCase AF: 0.00578

EpiControl AF: 0.00587

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.6
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.64
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	0.19	T
Polyphen		0.0080	B
Vest4		0.12
MutPred		0.34		Gain of glycosylation at S437 (P = 0.0158)
ClinPred		0.0063	T
GERP RS		-2.3
Varity_R		0.12
gMVP		0.25
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs60582583; hg19: chr4-5755516;