4-5753941-A-G

Variant names:

• chr4-5753941-A-G
• rs116236414
• NM_153717.3:c.1464+8A>G

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.1464+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,612,628 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (21 hom.)
• Consequence: EVC NM_153717.3 splice_region, intron
• Scores: Splicing: ADA: 0.0003016
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.54
• Publications: 1 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 (BayesDel_noAF=-0.9).
• BP6: Variant 4-5753941-A-G is Benign according to our data. Variant chr4-5753941-A-G is described in ClinVar as Benign. ClinVar VariationId is 506351.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 = 0.0108 (1644/152322) while in subpopulation AFR AF = 0.0371 (1543/41578). AF 95% confidence interval is 0.0356. There are 34 homozygotes in GnomAd4. There are 781 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 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.1464+8A>G		splice_region intron	N/A	NP_714928.1	P57679
	EVC	NM_001306090.2		c.1464+8A>G		splice_region intron	N/A	NP_001293019.1
	EVC	NM_001306092.2		c.1464+8A>G		splice_region intron	N/A	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.1464+8A>G		splice_region intron	N/A	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.1464+8A>G		splice_region intron	N/A	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.1464+8A>G		splice_region intron	N/A	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1644 AN: 152204 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00289 AC: 726 AN: 250868 AF XY: 0.00207

Gnomad AFR exome AF: 0.0401

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00104 AC: 1517 AN: 1460306 Hom.: 21 Cov.: 35 AF XY: 0.000925 AC XY: 672 AN XY: 726484

African (AFR) AF: 0.0369 AC: 1232 AN: 33422

American (AMR) AF: 0.00203 AC: 91 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00128 AC: 6 AN: 4680

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111968

Other (OTH) AF: 0.00244 AC: 147 AN: 60274

GnomAD4 genome AF: 0.0108 AC: 1644 AN: 152322 Hom.: 34 Cov.: 33 AF XY: 0.0105 AC XY: 781 AN XY: 74484

African (AFR) AF: 0.0371 AC: 1543 AN: 41578

American (AMR) AF: 0.00490 AC: 75 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00707 Hom.: 5

Bravo AF: 0.0129

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.41
PhyloP100		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.036
SpliceAI score (max)		0.18		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: rs116236414; hg19: chr4-5755668;