rs111293777

Variant names:

• chr4-5793686-G-A
• rs111293777
• NM_153717.3:c.1855G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_153717.3(EVC):​c.1855G>A​(p.Val619Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000795 in 1,551,356 control chromosomes in the GnomAD database, including 12 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 Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V619A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (7 hom.)
• Consequence: EVC NM_153717.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.47
• Publications: 4 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008758903).
• BP6: Variant 4-5793686-G-A is Benign according to our data. Variant chr4-5793686-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 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.1855G>A	p.Val619Ile	missense	Exon 13 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.1855G>A	p.Val619Ile	missense	Exon 13 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.1855G>A	p.Val619Ile	missense	Exon 13 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000861182.1		c.1855G>A	p.Val619Ile	missense	Exon 13 of 21	ENSP00000531241.1
	EVC	ENST00000960562.1		c.1717G>A	p.Val573Ile	missense	Exon 12 of 20	ENSP00000630621.1

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 494 AN: 152192 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00117 AC: 185 AN: 157494 AF XY: 0.00113

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.000563

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000873

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000656

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000526 AC: 736 AN: 1399046 Hom.: 7 Cov.: 32 AF XY: 0.000554 AC XY: 382 AN XY: 690130

African (AFR) AF: 0.0153 AC: 486 AN: 31732

American (AMR) AF: 0.000502 AC: 18 AN: 35876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25190

East Asian (EAS) AF: 0.00 AC: 0 AN: 35878

South Asian (SAS) AF: 0.00199 AC: 158 AN: 79224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49368

Middle Eastern (MID) AF: 0.000694 AC: 3 AN: 4320

European-Non Finnish (NFE) AF: 0.0000176 AC: 19 AN: 1079548

Other (OTH) AF: 0.000898 AC: 52 AN: 57910

GnomAD4 genome AF: 0.00327 AC: 498 AN: 152310 Hom.: 5 Cov.: 33 AF XY: 0.00338 AC XY: 252 AN XY: 74482

African (AFR) AF: 0.0111 AC: 463 AN: 41584

American (AMR) AF: 0.000850 AC: 13 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

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

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.000703 Hom.: 1

Bravo AF: 0.00382

ESP6500AA AF: 0.0106 AC: 46

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00104 AC: 98

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.12
Sift	Benign	0.033	D
Sift4G	Uncertain	0.035	D
Polyphen		0.99	D
Vest4		0.33
MVP		0.54
ClinPred		0.022	T
GERP RS		5.2
Varity_R		0.094
gMVP		0.078
Mutation Taster		=98/2	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: rs111293777; hg19: chr4-5795413; COSMIC: COSV99059891;