chr4-5741782-C-T

Variant names:

• chr4-5741782-C-T
• rs6446393
• NM_153717.3:c.769C>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.769C>T​(p.Leu257Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.941 in 1,552,778 control chromosomes in the GnomAD database, including 687,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L257L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.96 (69532 hom., cov: 33)
  • Exomes 𝑓: 0.94 (617958 hom.)
• Consequence: EVC NM_153717.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.00
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-5741782-C-T is Benign according to our data. Variant chr4-5741782-C-T is described in ClinVar as Benign. ClinVar VariationId is 198281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.981 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.769C>T	p.Leu257Leu	synonymous	Exon 6 of 21	NP_714928.1	P57679
	EVC	NM_001306090.2		c.769C>T	p.Leu257Leu	synonymous	Exon 6 of 21	NP_001293019.1
	EVC	NM_001306092.2		c.769C>T	p.Leu257Leu	synonymous	Exon 6 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.769C>T	p.Leu257Leu	synonymous	Exon 6 of 21	ENSP00000264956.6	P57679
	EVC	ENST00000509451.1	TSL:1	c.769C>T	p.Leu257Leu	synonymous	Exon 6 of 12	ENSP00000426774.1	E9PCN4
	EVC	ENST00000861182.1		c.769C>T	p.Leu257Leu	synonymous	Exon 6 of 21	ENSP00000531241.1

Frequencies

GnomAD3 genomes AF: 0.955 AC: 145268 AN: 152090 Hom.: 69466 Cov.: 33

Gnomad AFR AF: 0.989

Gnomad AMI AF: 0.939

Gnomad AMR AF: 0.968

Gnomad ASJ AF: 0.931

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.911

Gnomad FIN AF: 0.959

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.954

GnomAD2 exomes AF: 0.948 AC: 237096 AN: 250044 AF XY: 0.944

Gnomad AFR exome AF: 0.991

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.936

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.954

Gnomad NFE exome AF: 0.935

Gnomad OTH exome AF: 0.943

GnomAD4 exome AF: 0.939 AC: 1314994 AN: 1400570 Hom.: 617958 Cov.: 26 AF XY: 0.937 AC XY: 656225 AN XY: 700004

African (AFR) AF: 0.991 AC: 32216 AN: 32498

American (AMR) AF: 0.981 AC: 43632 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 23912 AN: 25638

East Asian (EAS) AF: 1.00 AC: 39227 AN: 39246

South Asian (SAS) AF: 0.908 AC: 76786 AN: 84558

European-Finnish (FIN) AF: 0.954 AC: 50714 AN: 53176

Middle Eastern (MID) AF: 0.919 AC: 4793 AN: 5218

European-Non Finnish (NFE) AF: 0.935 AC: 988839 AN: 1057566

Other (OTH) AF: 0.943 AC: 54875 AN: 58202

GnomAD4 genome AF: 0.955 AC: 145394 AN: 152208 Hom.: 69532 Cov.: 33 AF XY: 0.956 AC XY: 71132 AN XY: 74408

African (AFR) AF: 0.990 AC: 41122 AN: 41558

American (AMR) AF: 0.968 AC: 14796 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.931 AC: 3229 AN: 3468

East Asian (EAS) AF: 0.999 AC: 5183 AN: 5188

South Asian (SAS) AF: 0.912 AC: 4397 AN: 4820

European-Finnish (FIN) AF: 0.959 AC: 10139 AN: 10576

Middle Eastern (MID) AF: 0.935 AC: 273 AN: 292

European-Non Finnish (NFE) AF: 0.932 AC: 63389 AN: 67998

Other (OTH) AF: 0.954 AC: 2013 AN: 2110

Alfa AF: 0.939 Hom.: 110115

Bravo AF: 0.960

Asia WGS AF: 0.957 AC: 3321 AN: 3470

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	-0.77
CADD	Benign	4.8
DANN	Benign	0.53
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs6446393; hg19: chr4-5743509; COSMIC: COSV108074601;