4-5748304-C-T

Variant names:

• chr4-5748304-C-T
• rs6854138
• NM_153717.3:c.1096C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_153717.3(EVC):​c.1096C>T​(p.Leu366Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00583 in 1,613,968 control chromosomes in the GnomAD database, including 423 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 0.030 (228 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (195 hom.)
• Consequence: EVC NM_153717.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.05192
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.683
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 4-5748304-C-T is Benign according to our data. Variant chr4-5748304-C-T is described in ClinVar as Benign. ClinVar VariationId is 262763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.683 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0999 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.1096C>T	p.Leu366Leu	splice_region synonymous	Exon 8 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.1096C>T	p.Leu366Leu	splice_region synonymous	Exon 8 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.1096C>T	p.Leu366Leu	splice_region synonymous	Exon 8 of 12	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.1096C>T	p.Leu366Leu	splice_region synonymous	Exon 8 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.1096C>T	p.Leu366Leu	splice_region synonymous	Exon 8 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.1096C>T	p.Leu366Leu	splice_region synonymous	Exon 8 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.0300 AC: 4564 AN: 152030 Hom.: 228 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.00781 AC: 1964 AN: 251332 AF XY: 0.00582

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00331 AC: 4832 AN: 1461820 Hom.: 195 Cov.: 35 AF XY: 0.00290 AC XY: 2107 AN XY: 727212

African (AFR) AF: 0.107 AC: 3582 AN: 33472

American (AMR) AF: 0.00631 AC: 282 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.000366 AC: 407 AN: 1111990

Other (OTH) AF: 0.00752 AC: 454 AN: 60390

GnomAD4 genome AF: 0.0301 AC: 4579 AN: 152148 Hom.: 228 Cov.: 32 AF XY: 0.0287 AC XY: 2132 AN XY: 74410

African (AFR) AF: 0.102 AC: 4253 AN: 41496

American (AMR) AF: 0.0137 AC: 209 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

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

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

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

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68010

Other (OTH) AF: 0.0227 AC: 48 AN: 2110

Alfa AF: 0.0121 Hom.: 50

Bravo AF: 0.0347

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Ellis-van Creveld syndrome (2)
-	-	2	not specified (2)
-	-	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	-0.66
CADD	Benign	17
DANN	Benign	0.73
PhyloP100		0.68
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.052
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.020		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: rs6854138; hg19: chr4-5750031;