rs3744997

chr18-45916200-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_020964.3(EPG5):c.3391A>G(p.Ile1131Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,608,738 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (9 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.45

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045704246).
• BP6: Variant 18-45916200-T-C is Benign according to our data. Variant chr18-45916200-T-C is described in ClinVar as [Benign]. Clinvar id is 466247.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000611 (93/152238) while in subpopulation EAS AF= 0.0141 (73/5180). AF 95% confidence interval is 0.0115. There are 0 homozygotes in gnomad4. There are 51 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.3391A>G	p.Ile1131Val	missense_variant	19/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.3391A>G	p.Ile1131Val	missense_variant	19/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000840 AC: 204 AN: 242738 Hom.: 0 AF XY: 0.000774 AC XY: 102 AN XY: 131784

Gnomad AFR exome AF: 0.000260

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0103

Gnomad SAS exome AF: 0.000238

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000901

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.000590 AC: 860 AN: 1456500 Hom.: 9 Cov.: 31 AF XY: 0.000530 AC XY: 384 AN XY: 724534

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0179

Gnomad4 SAS exome AF: 0.000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000756

Gnomad4 OTH exome AF: 0.000666

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74432

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000913 Hom.: 0

Bravo AF: 0.000589

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000977 AC: 118

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.080
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	13
Dann	Benign	0.88
DEOGEN2	Benign	0.0095	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.80	D
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;N
MutationTaster	Benign	0.72	D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.42	N;.
REVEL	Benign	0.019
Sift	Benign	0.37	T;.
Sift4G	Benign	0.74	T;.
Polyphen		0.037	B;B
Vest4		0.098
MVP		0.24
MPC		0.39
ClinPred		0.017	T
GERP RS		2.1
Varity_R		0.020
gMVP		0.090

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: rs3744997; hg19: chr18-43496165;