rs35287723

Variant names:

• chr4-5810428-G-A
• rs35287723
• NM_153717.3:c.2872G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-5810428-G-A
• chr4-5810428-G-C
• chr4-5810428-G-T

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.2872G>A​(p.Asp958Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,612,624 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D958Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0091 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (16 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.17
• Publications: 0 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=0.0033895671).
• BP6: Variant 4-5810428-G-A is Benign according to our data. Variant chr4-5810428-G-A is described in ClinVar as Benign. ClinVar VariationId is 349211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00911 (1387/152280) while in subpopulation AFR AF = 0.0317 (1319/41562). AF 95% confidence interval is 0.0303. There are 21 homozygotes in GnomAd4. There are 637 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.2872G>A	p.Asp958Asn	missense	Exon 20 of 21	NP_714928.1
	EVC	NM_001306090.2		c.2872G>A	p.Asp958Asn	missense	Exon 20 of 21	NP_001293019.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	ENST00000264956.11	TSL:1 MANE Select	c.2872G>A	p.Asp958Asn	missense	Exon 20 of 21	ENSP00000264956.6
	EVC	ENST00000861182.1		c.2872G>A	p.Asp958Asn	missense	Exon 20 of 21	ENSP00000531241.1
	EVC	ENST00000960562.1		c.2734G>A	p.Asp912Asn	missense	Exon 19 of 20	ENSP00000630621.1

Frequencies

GnomAD3 genomes AF: 0.00909 AC: 1383 AN: 152162 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00235 AC: 580 AN: 246510 AF XY: 0.00191

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000144

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.000933 AC: 1362 AN: 1460344 Hom.: 16 Cov.: 32 AF XY: 0.000845 AC XY: 614 AN XY: 726282

African (AFR) AF: 0.0327 AC: 1093 AN: 33464

American (AMR) AF: 0.00166 AC: 74 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5766

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111616

Other (OTH) AF: 0.00201 AC: 121 AN: 60314

GnomAD4 genome AF: 0.00911 AC: 1387 AN: 152280 Hom.: 21 Cov.: 33 AF XY: 0.00856 AC XY: 637 AN XY: 74456

African (AFR) AF: 0.0317 AC: 1319 AN: 41562

American (AMR) AF: 0.00288 AC: 44 AN: 15296

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68018

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00437 Hom.: 4

Bravo AF: 0.00990

ESP6500AA AF: 0.0302 AC: 133

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00269 AC: 326

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (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	Benign	0.077
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.098
Sift	Benign	0.86	T
Sift4G	Benign	0.84	T
Polyphen		0.23	B
Vest4		0.058
MVP		0.57
ClinPred		0.017	T
GERP RS		4.3
Varity_R		0.057
gMVP		0.10
Mutation Taster		=100/0	polymorphism

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: rs35287723; hg19: chr4-5812155; COSMIC: COSV99059879;