rs141859946

Variant names:

• chr4-5753838-G-A
• rs141859946
• NM_153717.3:c.1369G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_153717.3(EVC):​c.1369G>A​(p.Glu457Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,614,114 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 2.55
• Publications: 7 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052634776).
• BP6: Variant 4-5753838-G-A is Benign according to our data. Variant chr4-5753838-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 349176.
• BS2: High Homozygotes in GnomAdExome4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVC	NM_153717.3	MANE Select	c.1369G>A	p.Glu457Lys	missense	Exon 10 of 21	NP_714928.1
	EVC	NM_001306090.2		c.1369G>A	p.Glu457Lys	missense	Exon 10 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.1369G>A	p.Glu457Lys	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.1369G>A	p.Glu457Lys	missense	Exon 10 of 21	ENSP00000264956.6
	EVC	ENST00000509451.1	TSL:1	c.1369G>A	p.Glu457Lys	missense	Exon 10 of 12	ENSP00000426774.1
	EVC	ENST00000514919.1	TSL:2	n.432G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 292 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00208 AC: 522 AN: 251470 AF XY: 0.00214

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00289

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00272 AC: 3970 AN: 1461820 Hom.: 8 Cov.: 35 AF XY: 0.00269 AC XY: 1956 AN XY: 727206

African (AFR) AF: 0.000508 AC: 17 AN: 33478

American (AMR) AF: 0.00148 AC: 66 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00727 AC: 190 AN: 26136

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

South Asian (SAS) AF: 0.000928 AC: 80 AN: 86250

European-Finnish (FIN) AF: 0.00103 AC: 55 AN: 53416

Middle Eastern (MID) AF: 0.0119 AC: 68 AN: 5732

European-Non Finnish (NFE) AF: 0.00298 AC: 3316 AN: 1111996

Other (OTH) AF: 0.00295 AC: 178 AN: 60388

GnomAD4 genome AF: 0.00192 AC: 292 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.00183 AC XY: 136 AN XY: 74472

African (AFR) AF: 0.000698 AC: 29 AN: 41548

American (AMR) AF: 0.00157 AC: 24 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00279 AC: 190 AN: 68032

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00273 Hom.: 1

Bravo AF: 0.00204

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00213 AC: 259

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00308

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Ellis-van Creveld syndrome (2)
-	1	1	Ellis-van Creveld syndrome;C0457013:Curry-Hall syndrome (2)
-	-	1	EVC-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.022	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.040
Sift	Benign	0.71	T
Sift4G	Benign	0.43	T
Polyphen		0.12	B
Vest4		0.23
MVP		0.48
ClinPred		0.017	T
GERP RS		5.0
Varity_R		0.13
gMVP		0.093
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141859946; hg19: chr4-5755565; COSMIC: COSV106090590;