rs61744077

Positions:

• chr18-45916098-T-C
• chr18-45916098-T-G

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.3493A>G​(p.Ile1165Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,614,080 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1165L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (6 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.63

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=0.0060216486).
• BP6: Variant 18-45916098-T-C is Benign according to our data. Variant chr18-45916098-T-C is described in ClinVar as [Benign]. Clinvar id is 534611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-45916098-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00615 (936/152234) while in subpopulation AFR AF= 0.0206 (857/41544). AF 95% confidence interval is 0.0195. There are 11 homozygotes in gnomad4. There are 451 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.3493A>G	p.Ile1165Val	missense_variant	19/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.3493A>G	p.Ile1165Val	missense_variant	19/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.00615 AC: 936 AN: 152116 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

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: 0.000103

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00148 AC: 370 AN: 249510 Hom.: 6 AF XY: 0.00103 AC XY: 140 AN XY: 135360

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000686 AC: 1003 AN: 1461846 Hom.: 6 Cov.: 31 AF XY: 0.000595 AC XY: 433 AN XY: 727228

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000773

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00615 AC: 936 AN: 152234 Hom.: 11 Cov.: 32 AF XY: 0.00606 AC XY: 451 AN XY: 74462

Gnomad4 AFR AF: 0.0206

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000927 Hom.: 2

Bravo AF: 0.00758

ESP6500AA AF: 0.0247 AC: 96

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00164 AC: 198

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

EPG5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2023

This variant is classified as 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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.73
DEOGEN2	Benign	0.0066	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.79	D
MetaRNN	Benign	0.0060	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N;N
MutationTaster	Benign	0.68	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.050	N;.
REVEL	Benign	0.044
Sift	Benign	0.73	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0030	B;B
Vest4		0.041
MVP		0.32
MPC		0.39
ClinPred		0.010	T
GERP RS		4.8
Varity_R		0.022
gMVP		0.053

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: rs61744077; hg19: chr18-43496063; COSMIC: COSV99030038;