dbSNP rs148641800: EPG5:p.Arg1322Leu (chr18-45912308-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.40

Publications

2 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

EPG5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPG5	NM_020964.3 link	c.3965G>T	p.Arg1322Leu	missense_variant	Exon 22 of 44	ENST00000282041.11	NP_066015.2	Q9HCE0-1Q9BTI0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPG5	ENST00000282041.11 link	c.3965G>T	p.Arg1322Leu	missense_variant	Exon 22 of 44	1	NM_020964.3	ENSP00000282041.4		Q9HCE0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000420

AC:

AN:

238354

AF XY:

0.00000769

show subpopulations

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:

AN:

1448650

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

720632

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32340

American (AMR)

AF:

0.00

AC:

AN:

40142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25476

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.00

AC:

AN:

84868

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1107558

Other (OTH)

AF:

0.0000335

AC:

AN:

59766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000339

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

1.9

L;L

PhyloP100

5.4

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-4.6

D;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.013

D;.

Polyphen

0.99

D;D

Vest4

0.84

MutPred

0.46

Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);

MVP

0.67

MPC

0.70

ClinPred

0.99

GERP RS

5.5

Varity_R

0.40

gMVP

0.64

Mutation Taster

=73/27

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over