rs148098259

chr18-45952604-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_020964.3(EPG5):c.1048C>T(p.Arg350Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00051 in 1,614,108 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R350L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (8 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.38

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010548562).
• BP6: Variant 18-45952604-G-A is Benign according to our data. Variant chr18-45952604-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 534613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00162 (247/152254) while in subpopulation AFR AF= 0.00542 (225/41542). AF 95% confidence interval is 0.00484. There are 0 homozygotes in gnomad4. There are 134 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.1048C>T	p.Arg350Cys	missense_variant	3/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.1048C>T	p.Arg350Cys	missense_variant	3/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000786 AC: 196 AN: 249450 Hom.: 0 AF XY: 0.000864 AC XY: 117 AN XY: 135340

Gnomad AFR exome AF: 0.00465

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00379

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000395 AC: 577 AN: 1461854 Hom.: 8 Cov.: 31 AF XY: 0.000518 AC XY: 377 AN XY: 727232

Gnomad4 AFR exome AF: 0.00523

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74452

Gnomad4 AFR AF: 0.00542

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000235 Hom.: 0

Bravo AF: 0.00142

ESP6500AA AF: 0.00422 AC: 16

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000894 AC: 108

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

EPG5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2021

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

Vici syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.0064
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.4	N;.
REVEL	Uncertain	0.39
Sift	Benign	0.19	T;.
Sift4G	Benign	0.12	T;.
Polyphen		0.038	B;B
Vest4		0.48
MVP		0.50
MPC		0.45
ClinPred		0.10	T
GERP RS		5.6
Varity_R		0.15
gMVP		0.45

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: rs148098259; hg19: chr18-43532570; COSMIC: COSV99957822;