rs78339727

chr18-45916574-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_020964.3(EPG5):c.3248C>T(p.Ser1083Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0294 in 1,596,020 control chromosomes in the GnomAD database, including 880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1083S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (59 hom., cov: 32)
  • Exomes 𝑓: 0.030 (821 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.89

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 -16 ACMG points.

• BP6: Variant 18-45916574-G-A is Benign according to our data. Variant chr18-45916574-G-A is described in ClinVar as [Benign]. Clinvar id is 466245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-45916574-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0214 (3256/152170) while in subpopulation SAS AF= 0.0415 (200/4816). AF 95% confidence interval is 0.0368. There are 59 homozygotes in gnomad4. There are 1606 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 58 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.3248C>T	p.Ser1083Leu	missense_variant	18/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.3248C>T	p.Ser1083Leu	missense_variant	18/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3258 AN: 152052 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.00645

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.0415

Gnomad FIN AF: 0.0363

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.0266 AC: 6592 AN: 247554 Hom.: 142 AF XY: 0.0285 AC XY: 3820 AN XY: 134254

Gnomad AFR exome AF: 0.00525

Gnomad AMR exome AF: 0.00735

Gnomad ASJ exome AF: 0.0234

Gnomad EAS exome AF: 0.00179

Gnomad SAS exome AF: 0.0479

Gnomad FIN exome AF: 0.0397

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0225

GnomAD4 exome AF: 0.0302 AC: 43652 AN: 1443850 Hom.: 821 Cov.: 31 AF XY: 0.0311 AC XY: 22205 AN XY: 713888

Gnomad4 AFR exome AF: 0.00494

Gnomad4 AMR exome AF: 0.00735

Gnomad4 ASJ exome AF: 0.0241

Gnomad4 EAS exome AF: 0.00322

Gnomad4 SAS exome AF: 0.0487

Gnomad4 FIN exome AF: 0.0396

Gnomad4 NFE exome AF: 0.0314

Gnomad4 OTH exome AF: 0.0260

GnomAD4 genome AF: 0.0214 AC: 3256 AN: 152170 Hom.: 59 Cov.: 32 AF XY: 0.0216 AC XY: 1606 AN XY: 74398

Gnomad4 AFR AF: 0.00643

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0242

Gnomad4 EAS AF: 0.00252

Gnomad4 SAS AF: 0.0415

Gnomad4 FIN AF: 0.0363

Gnomad4 NFE AF: 0.0307

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0273 Hom.: 36

Bravo AF: 0.0180

TwinsUK AF: 0.0343 AC: 127

ALSPAC AF: 0.0272 AC: 105

ESP6500AA AF: 0.00665 AC: 27

ESP6500EA AF: 0.0276 AC: 231

ExAC AF: 0.0276 AC: 3339

Asia WGS AF: 0.0160 AC: 55 AN: 3478

EpiCase AF: 0.0305

EpiControl AF: 0.0281

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2018

- -

Vici syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.84	D
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Benign	0.18
Sift	Uncertain	0.019	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		1.0	D;D
Vest4		0.13
MPC		0.15
ClinPred		0.017	T
GERP RS		5.8
Varity_R		0.096
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs78339727; hg19: chr18-43496539; COSMIC: COSV56348168; COSMIC: COSV56348168;