rs201067154

chr18-45955188-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020964.3(EPG5):c.214G>A(p.Ala72Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,614,154 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (7 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.486

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003615111).
• BP6: Variant 18-45955188-C-T is Benign according to our data. Variant chr18-45955188-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 466241.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr18-45955188-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00136 (1984/1461884) while in subpopulation SAS AF= 0.00246 (212/86258). AF 95% confidence interval is 0.00219. There are 7 homozygotes in gnomad4_exome. There are 970 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPG5	NM_020964.3	c.214G>A	p.Ala72Thr	missense_variant	2/44	ENST00000282041.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPG5	ENST00000282041.11	c.214G>A	p.Ala72Thr	missense_variant	2/44	1	NM_020964.3	P4

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00112 AC: 279 AN: 249544 Hom.: 2 AF XY: 0.00131 AC XY: 178 AN XY: 135386

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000782

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00281

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.00136 AC: 1984 AN: 1461884 Hom.: 7 Cov.: 32 AF XY: 0.00133 AC XY: 970 AN XY: 727242

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00246

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.000933 AC: 142 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74462

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.000865

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00242 AC: 20

ExAC AF: 0.00127 AC: 154

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	EPG5: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Vici syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	EPG5 NM_020964.2 exon2 p.Ala72Thr (c.214G>A): This variant has not been reported in the literature but is present in 0.3% (86/30602) of South Asian alleles including 2 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/18-43535154-C-T). This variant is present in ClinVar (Variation ID:466241). This variant amino acid threonine (Thr) is present in 4 species (alpaca, platypus, saker falcon, peregrine falcon) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

EPG5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0063	T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.092	N
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.74	N;.
REVEL	Benign	0.095
Sift	Benign	0.046	D;.
Sift4G	Benign	0.90	T;.
Polyphen		0.0030	B;B
Vest4		0.14
MVP		0.088
MPC		0.15
ClinPred		0.00041	T
GERP RS		2.1
Varity_R		0.024
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201067154; hg19: chr18-43535154;