rs549760994

chr18-45934877-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020964.3(EPG5):c.2189T>C(p.Val730Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000737 in 1,614,178 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V730L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (1 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.06

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010371745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.2189T>C	p.Val730Ala	missense_variant	11/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.2189T>C	p.Val730Ala	missense_variant	11/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 249488 Hom.: 0 AF XY: 0.0000886 AC XY: 12 AN XY: 135366

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461868 Hom.: 1 Cov.: 30 AF XY: 0.0000701 AC XY: 51 AN XY: 727238

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74488

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.000325

ExAC AF: 0.000116 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vici syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 20, 2022	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 730 of the EPG5 protein (p.Val730Ala). This variant is present in population databases (rs549760994, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with EPG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 579995). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EPG5 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 18, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2020

The c.2189T>C (p.V730A) alteration is located in exon 11 (coding exon 11) of the EPG5 gene. This alteration results from a T to C substitution at nucleotide position 2189, causing the valine (V) at amino acid position 730 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	1.3
Dann	Benign	0.94
DEOGEN2	Benign	0.0046	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.43	N
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.1	N;N
MutationTaster	Benign	0.79	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.87	N;.
REVEL	Benign	0.046
Sift	Benign	0.46	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;B
Vest4		0.11
MVP		0.085
MPC		0.18
ClinPred		0.0061	T
GERP RS		-2.5
Varity_R		0.026
gMVP		0.11

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: rs549760994; hg19: chr18-43514843;