rs200910594

Variant names:

• chr18-45954728-C-G
• rs200910594
• NM_020964.3:c.674G>C
• EPG5 p.Gly225Ala

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_020964.3(EPG5):​c.674G>C​(p.Gly225Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G225G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.338
• Publications: 1 publications found

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]

EPG5 Gene-Disease associations (from GenCC):

• Vici syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045568317).
• BP6: Variant 18-45954728-C-G is Benign according to our data. Variant chr18-45954728-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 581573.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020964.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	NM_020964.3	MANE Select	c.674G>C	p.Gly225Ala	missense	Exon 2 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.674G>C	p.Gly225Ala	missense	Exon 2 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.674G>C	p.Gly225Ala	missense	Exon 2 of 44	NP_001397787.1	A0A8Q3SIJ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	ENST00000282041.11	TSL:1 MANE Select	c.674G>C	p.Gly225Ala	missense	Exon 2 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.674G>C		non_coding_transcript_exon	Exon 2 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000587974.1	TSL:1	n.709G>C		non_coding_transcript_exon	Exon 2 of 24

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000402 AC: 10 AN: 248940 AF XY: 0.0000444

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000930 AC: 136 AN: 1461688 Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1111972

Other (OTH) AF: 0.000116 AC: 7 AN: 60388

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000910 Hom.: 0

Bravo AF: 0.0000453

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.32
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.34
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.39	N
REVEL	Benign	0.030
Sift	Benign	0.55	T
Sift4G	Benign	0.32	T
Varity_R		0.064
gMVP		0.22
Mutation Taster		=97/3	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs200910594;

hg19: chr18-43534694;