4-5711346-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_153717.3(EVC):c.-35C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,006,604 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (20 hom.)
• Consequence: EVC NM_153717.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0920

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EVC	NM_153717.3	c.-35C>A		5_prime_UTR_variant	1/21	ENST00000264956.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EVC	ENST00000264956.11	c.-35C>A		5_prime_UTR_variant	1/21	1	NM_153717.3	P1
EVC	ENST00000509451.1	c.-35C>A		5_prime_UTR_variant	1/12	1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 414 AN: 150808 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000872

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000925

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00520

Gnomad OTH AF: 0.00193

GnomAD3 exomes AF: 0.00730 AC: 2 AN: 274 Hom.: 0 AF XY: 0.0130 AC XY: 2 AN XY: 154

Gnomad NFE exome AF: 0.00746

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00650 AC: 5564 AN: 855688 Hom.: 20 Cov.: 28 AF XY: 0.00653 AC XY: 2597 AN XY: 397772

Gnomad4 AFR exome AF: 0.000738

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00105

Gnomad4 EAS exome AF: 0.000209

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00115

Gnomad4 NFE exome AF: 0.00691

Gnomad4 OTH exome AF: 0.00580

GnomAD4 genome AF: 0.00274 AC: 414 AN: 150916 Hom.: 1 Cov.: 32 AF XY: 0.00249 AC XY: 184 AN XY: 73774

Gnomad4 AFR AF: 0.000870

Gnomad4 AMR AF: 0.000924

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000200

Gnomad4 NFE AF: 0.00521

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.000374 Hom.: 0

Bravo AF: 0.00300

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ellis-van Creveld syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	11
Dann	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs546318095; hg19: chr4-5713073;