18-45866897-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020964.3(EPG5):c.6522G>A(p.Pro2174=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,613,994 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (103 hom.)
• Consequence: EPG5 NM_020964.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.13

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 18-45866897-C-T is Benign according to our data. Variant chr18-45866897-C-T is described in ClinVar as [Benign]. Clinvar id is 534619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.007 (1066/152268) while in subpopulation NFE AF= 0.0116 (791/68022). AF 95% confidence interval is 0.011. There are 8 homozygotes in gnomad4. There are 504 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.6522G>A	p.Pro2174=	synonymous_variant	38/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.6522G>A	p.Pro2174=	synonymous_variant	38/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1066 AN: 152150 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00677 AC: 1688 AN: 249492 Hom.: 13 AF XY: 0.00699 AC XY: 946 AN XY: 135352

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00768

Gnomad FIN exome AF: 0.00515

Gnomad NFE exome AF: 0.00996

Gnomad OTH exome AF: 0.00643

GnomAD4 exome AF: 0.0106 AC: 15527 AN: 1461726 Hom.: 103 Cov.: 32 AF XY: 0.0105 AC XY: 7654 AN XY: 727182

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00532

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00685

Gnomad4 FIN exome AF: 0.00490

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.00700 AC: 1066 AN: 152268 Hom.: 8 Cov.: 32 AF XY: 0.00677 AC XY: 504 AN XY: 74450

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00945 Hom.: 1

Bravo AF: 0.00657

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0103

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

EPG5: BP4, BP7, BS1, BS2 -

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
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.061
Dann	Benign	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: rs148683476; hg19: chr18-43446862; COSMIC: COSV56346655;