chr18-45912308-C-A

Variant names:

• chr18-45912308-C-A
• rs148641800
• NM_020964.3:c.3965G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020964.3(EPG5):​c.3965G>T​(p.Arg1322Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000483 in 1,448,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1322H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.40
• Publications: 2 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: ClinGen, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

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.3965G>T	p.Arg1322Leu	missense	Exon 22 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.3965G>T	p.Arg1322Leu	missense	Exon 22 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.3965G>T	p.Arg1322Leu	missense	Exon 22 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.3965G>T	p.Arg1322Leu	missense	Exon 22 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.3965G>T		non_coding_transcript_exon	Exon 22 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000587974.1	TSL:1	n.4000G>T		non_coding_transcript_exon	Exon 22 of 24

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 238354 AF XY: 0.00000769

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: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1448650 Hom.: 0 Cov.: 31 AF XY: 0.00000555 AC XY: 4 AN XY: 720632

African (AFR) AF: 0.00 AC: 0 AN: 32340

American (AMR) AF: 0.00 AC: 0 AN: 40142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25476

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 84868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1107558

Other (OTH) AF: 0.0000335 AC: 2 AN: 59766

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000339 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.9	L
PhyloP100		5.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.46		Loss of solvent accessibility (P = 0.1077)
MVP		0.67
MPC		0.70
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.40
gMVP		0.64
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs148641800; hg19: chr18-43492273;