rs200114829

chr18-45922360-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_020964.3(EPG5):c.3079A>G(p.Met1027Val) variant causes a missense change. The variant allele was found at a frequency of 0.000159 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.24

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010077685).
• BP6: Variant 18-45922360-T-C is Benign according to our data. Variant chr18-45922360-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 534610.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 = 0.000932 (142/152300) while in subpopulation AFR AF= 0.00315 (131/41562). AF 95% confidence interval is 0.00271. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.3079A>G	p.Met1027Val	missense_variant	16/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.3079A>G	p.Met1027Val	missense_variant	16/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000216 AC: 54 AN: 249496 Hom.: 0 AF XY: 0.000163 AC XY: 22 AN XY: 135366

Gnomad AFR exome AF: 0.00304

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000787 AC: 115 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41 AN XY: 727236

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74468

Gnomad4 AFR AF: 0.00315

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000903

ESP6500AA AF: 0.00229 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000240 AC: 29

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

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

Mar 21, 2023

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2020

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar as likely benign but additional evidence is not available (SCV000763877.1; Landrum et al., 2016); Observed in 0.0324% (91/280904 alleles) in large population cohorts (Lek et al., 2016) -

Vici syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Benign	0.047	T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N;.
REVEL	Benign	0.099
Sift	Benign	0.20	T;.
Sift4G	Benign	0.40	T;.
Polyphen		0.0010	B;B
Vest4		0.32
MVP		0.30
MPC		0.15
ClinPred		0.013	T
GERP RS		4.3
Varity_R		0.095
gMVP		0.66

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: rs200114829; hg19: chr18-43502326; COSMIC: COSV56349184; COSMIC: COSV56349184;