rs2286343

Variant names:

• chr4-5745345-C-T
• rs2286343
• NM_153717.3:c.939+4C>T

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.939+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,612,486 control chromosomes in the GnomAD database, including 96,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9303 hom., cov: 31)
  • Exomes 𝑓: 0.34 (87222 hom.)
• Consequence: EVC NM_153717.3 splice_region, intron
• Scores: Splicing: ADA: 0.01367
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.69
• Publications: 18 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]

EVC Gene-Disease associations (from GenCC):

• acrofacial dysostosis, Weyers type

  Inheritance: AR, Unknown, AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-5745345-C-T is Benign according to our data. Variant chr4-5745345-C-T is described in ClinVar as Benign. ClinVar VariationId is 262785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 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.939+4C>T		splice_region intron	N/A	NP_714928.1	P57679
	EVC	NM_001306090.2		c.939+4C>T		splice_region intron	N/A	NP_001293019.1
	EVC	NM_001306092.2		c.939+4C>T		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.939+4C>T		splice_region intron	N/A	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.939+4C>T		splice_region intron	N/A	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.939+4C>T		splice_region intron	N/A	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51696 AN: 150980 Hom.: 9309 Cov.: 31

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.349

GnomAD2 exomes AF: 0.382 AC: 96022 AN: 251298 AF XY: 0.379

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.525

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.649

Gnomad FIN exome AF: 0.332

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.338 AC: 493256 AN: 1461388 Hom.: 87222 Cov.: 43 AF XY: 0.340 AC XY: 246919 AN XY: 726990

African (AFR) AF: 0.289 AC: 9668 AN: 33470

American (AMR) AF: 0.512 AC: 22899 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 8026 AN: 26126

East Asian (EAS) AF: 0.662 AC: 26276 AN: 39684

South Asian (SAS) AF: 0.406 AC: 35056 AN: 86248

European-Finnish (FIN) AF: 0.336 AC: 17922 AN: 53378

Middle Eastern (MID) AF: 0.380 AC: 2187 AN: 5760

European-Non Finnish (NFE) AF: 0.315 AC: 350635 AN: 1111646

Other (OTH) AF: 0.341 AC: 20587 AN: 60376

GnomAD4 genome AF: 0.342 AC: 51725 AN: 151098 Hom.: 9303 Cov.: 31 AF XY: 0.349 AC XY: 25754 AN XY: 73792

African (AFR) AF: 0.293 AC: 11958 AN: 40868

American (AMR) AF: 0.438 AC: 6679 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1068 AN: 3470

East Asian (EAS) AF: 0.651 AC: 3330 AN: 5118

South Asian (SAS) AF: 0.415 AC: 1981 AN: 4772

European-Finnish (FIN) AF: 0.334 AC: 3505 AN: 10480

Middle Eastern (MID) AF: 0.342 AC: 100 AN: 292

European-Non Finnish (NFE) AF: 0.324 AC: 22015 AN: 67856

Other (OTH) AF: 0.349 AC: 730 AN: 2092

Alfa AF: 0.329 Hom.: 16773

Bravo AF: 0.348

Asia WGS AF: 0.508 AC: 1762 AN: 3478

EpiCase AF: 0.329

EpiControl AF: 0.331

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.79
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.086
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2286343; hg19: chr4-5747072; COSMIC: COSV53833302; COSMIC: COSV53833302;