rs35953626

Variant names:

• chr4-5753797-G-A
• rs35953626
• NM_153717.3:c.1328G>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.1328G>A​(p.Arg443Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,614,078 control chromosomes in the GnomAD database, including 2,137 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. R443R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.067 (1127 hom., cov: 34)
  • Exomes 𝑓: 0.0072 (1010 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:13
• Conservation: PhyloP100: 0.112
• 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=0.0012990832).
• BP6: Variant 4-5753797-G-A is Benign according to our data. Variant chr4-5753797-G-A is described in ClinVar as Benign. ClinVar VariationId is 5342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.223 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.1328G>A	p.Arg443Gln	missense	Exon 10 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.1328G>A	p.Arg443Gln	missense	Exon 10 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.1328G>A	p.Arg443Gln	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.1328G>A	p.Arg443Gln	missense	Exon 10 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.1328G>A	p.Arg443Gln	missense	Exon 10 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.1328G>A	p.Arg443Gln	missense	Exon 10 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.0665 AC: 10108 AN: 152114 Hom.: 1122 Cov.: 34

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0345

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.0555

GnomAD2 exomes AF: 0.0176 AC: 4418 AN: 251456 AF XY: 0.0129

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00720 AC: 10530 AN: 1461846 Hom.: 1010 Cov.: 30 AF XY: 0.00626 AC XY: 4549 AN XY: 727216

African (AFR) AF: 0.235 AC: 7864 AN: 33476

American (AMR) AF: 0.0141 AC: 630 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.0141 AC: 81 AN: 5756

European-Non Finnish (NFE) AF: 0.000769 AC: 855 AN: 1111994

Other (OTH) AF: 0.0172 AC: 1039 AN: 60396

GnomAD4 genome AF: 0.0666 AC: 10140 AN: 152232 Hom.: 1127 Cov.: 34 AF XY: 0.0643 AC XY: 4787 AN XY: 74444

African (AFR) AF: 0.226 AC: 9401 AN: 41512

American (AMR) AF: 0.0344 AC: 527 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

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

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68028

Other (OTH) AF: 0.0549 AC: 116 AN: 2112

Alfa AF: 0.0274 Hom.: 1068

Bravo AF: 0.0778

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.225 AC: 991

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0210 AC: 2553

Asia WGS AF: 0.0150 AC: 54 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00184

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	3	Ellis-van Creveld syndrome (4)
-	-	3	not provided (3)
-	-	1	Curry-Hall syndrome (1)
-	-	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.082	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.11
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.058
Sift	Benign	0.71	T
Sift4G	Benign	0.80	T
Polyphen		0.27	B
Vest4		0.079
ClinPred		0.0067	T
GERP RS		1.1
Varity_R		0.042
gMVP		0.049
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35953626; hg19: chr4-5755524; COSMIC: COSV53834162;