rs34064739

chr18-45880151-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020964.3(EPG5):c.5591G>A(p.Ser1864Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00914 in 1,611,596 control chromosomes in the GnomAD database, including 1,157 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1864R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.049 (605 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (552 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.279

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012777448).
• BP6: Variant 18-45880151-C-T is Benign according to our data. Variant chr18-45880151-C-T is described in ClinVar as [Benign]. Clinvar id is 466257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-45880151-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.5591G>A	p.Ser1864Asn	missense_variant	32/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.5591G>A	p.Ser1864Asn	missense_variant	32/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7430 AN: 152108 Hom.: 602 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0125 AC: 3072 AN: 244996 Hom.: 231 AF XY: 0.00930 AC XY: 1245 AN XY: 133882

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.00865

Gnomad ASJ exome AF: 0.00623

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000419

Gnomad OTH exome AF: 0.00551

GnomAD4 exome AF: 0.00500 AC: 7296 AN: 1459370 Hom.: 552 Cov.: 31 AF XY: 0.00429 AC XY: 3115 AN XY: 725820

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.00984

Gnomad4 ASJ exome AF: 0.00563

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000256

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.0489 AC: 7442 AN: 152226 Hom.: 605 Cov.: 32 AF XY: 0.0477 AC XY: 3547 AN XY: 74418

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.0195

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0103 Hom.: 136

Bravo AF: 0.0559

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.154 AC: 578

ESP6500EA AF: 0.00159 AC: 13

ExAC AF: 0.0149 AC: 1800

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 31, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Vici syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	6.9
Dann	Benign	0.90
DEOGEN2	Benign	0.0045	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0041	N
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.76	N;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.69	N;.
REVEL	Benign	0.064
Sift	Benign	0.61	T;.
Sift4G	Benign	0.067	T;.
Polyphen		0.0010	B;B
Vest4		0.046
MPC		0.15
ClinPred		0.0013	T
GERP RS		-2.5
Varity_R		0.046
gMVP		0.14

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: rs34064739; hg19: chr18-43460116;