rs139209033

chr18-45901101-G-A

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.4541C>T(p.Pro1514Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,614,168 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1514P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.293

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=0.0033112466).
• BP6: Variant 18-45901101-G-A is Benign according to our data. Variant chr18-45901101-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 534612.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 = 0.00129 (196/152314) while in subpopulation AFR AF= 0.00411 (171/41568). AF 95% confidence interval is 0.00361. There are 0 homozygotes in gnomad4. There are 94 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.4541C>T	p.Pro1514Leu	missense_variant	26/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.4541C>T	p.Pro1514Leu	missense_variant	26/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000385 AC: 96 AN: 249336 Hom.: 1 AF XY: 0.000311 AC XY: 42 AN XY: 135264

Gnomad AFR exome AF: 0.00491

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.000190 AC: 278 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 127 AN XY: 727232

Gnomad4 AFR exome AF: 0.00397

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000107

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74476

Gnomad4 AFR AF: 0.00411

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000404 Hom.: 1

Bravo AF: 0.00135

ESP6500AA AF: 0.00394 AC: 16

ESP6500EA AF: 0.000240 AC: 2

ExAC AF: 0.000579 AC: 70

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

EPG5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 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). -

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
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	12
Dann	Benign	0.31
DEOGEN2	Benign	0.016	T;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.13	N
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.020
Sift	Benign	0.85	T;.
Sift4G	Benign	0.81	T;.
Polyphen		0.0030	B;B
Vest4		0.14
MVP		0.13
MPC		0.15
ClinPred		0.0042	T
GERP RS		1.6
Varity_R		0.021
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139209033; hg19: chr18-43481066; COSMIC: COSV56348501;