rs200372908

chr18-45880159-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020964.3(EPG5):c.5583C>T(p.Cys1861=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,611,458 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: EPG5 NM_020964.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.583

Genes affected

EPG5 (HGNC:29331): (ectopic P-granules 5 autophagy tethering factor) This gene encodes a large coiled coil domain-containing protein that functions in autophagy during starvation conditions. Mutations in this gene cause Vici syndrome. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 18-45880159-G-A is Benign according to our data. Variant chr18-45880159-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 466255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-45880159-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.583 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0038 (578/152286) while in subpopulation AFR AF= 0.00864 (359/41572). AF 95% confidence interval is 0.0079. There are 3 homozygotes in gnomad4. There are 309 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.5583C>T	p.Cys1861=	synonymous_variant	32/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.5583C>T	p.Cys1861=	synonymous_variant	32/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 579 AN: 152168 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00238 AC: 581 AN: 244328 Hom.: 0 AF XY: 0.00234 AC XY: 313 AN XY: 133636

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000225

Gnomad SAS exome AF: 0.00243

Gnomad FIN exome AF: 0.00758

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.00196 AC: 2853 AN: 1459172 Hom.: 6 Cov.: 31 AF XY: 0.00202 AC XY: 1469 AN XY: 725728

Gnomad4 AFR exome AF: 0.00820

Gnomad4 AMR exome AF: 0.000605

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00315

Gnomad4 FIN exome AF: 0.00697

Gnomad4 NFE exome AF: 0.00162

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00380 AC: 578 AN: 152286 Hom.: 3 Cov.: 32 AF XY: 0.00415 AC XY: 309 AN XY: 74448

Gnomad4 AFR AF: 0.00864

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00941

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00224 Hom.: 1

Bravo AF: 0.00350

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00186

EpiControl AF: 0.00142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	EPG5: BP4, BP7 -

EPG5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Vici syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	1.2
Dann	Benign	0.92

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: rs200372908; hg19: chr18-43460124;