rs140494095

chr18-45954662-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020964.3(EPG5):c.740C>T(p.Pro247Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00193 in 1,614,216 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts 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. P247P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (51 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.89

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0067515373).
• BP6: Variant 18-45954662-G-A is Benign according to our data. Variant chr18-45954662-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 466264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-45954662-G-A is described in Lovd as [Likely_benign]. Variant chr18-45954662-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00281 (428/152332) while in subpopulation AMR AF= 0.0156 (239/15298). AF 95% confidence interval is 0.014. There are 2 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.740C>T	p.Pro247Leu	missense_variant	2/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.740C>T	p.Pro247Leu	missense_variant	2/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152214 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0138

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00660 AC: 1646 AN: 249442 Hom.: 32 AF XY: 0.00521 AC XY: 705 AN XY: 135326

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.0350

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0133

Gnomad SAS exome AF: 0.00441

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000972

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00184 AC: 2695 AN: 1461884 Hom.: 51 Cov.: 32 AF XY: 0.00169 AC XY: 1229 AN XY: 727242

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.0330

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0149

Gnomad4 SAS exome AF: 0.00405

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000755

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00329 AC XY: 245 AN XY: 74482

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0135

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.000892 Hom.: 1

Bravo AF: 0.00414

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000705 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00563 AC: 682

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Vici syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 17, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.035	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0068	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.3	N;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.50
MVP		0.36
MPC		0.64
ClinPred		0.012	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.49

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: rs140494095; hg19: chr18-43534628; COSMIC: COSV56346434;