dbSNP rs145177562: EPG5:p.Ser35Thr (chr18-45955298-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020964.3(EPG5):c.104G>C(p.Ser35Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,588 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S35N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EPG5
NM_020964.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.880

Publications

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

EPG5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061113983).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPG5	NM_020964.3	MANE Select	c.104G>C	p.Ser35Thr	missense	Exon 2 of 44	NP_066015.2	Q9HCE0-1
EPG5	NM_001410859.1		c.104G>C	p.Ser35Thr	missense	Exon 2 of 44	NP_001397788.1	A0A8Q3SIU6
EPG5	NM_001410858.1		c.104G>C	p.Ser35Thr	missense	Exon 2 of 44	NP_001397787.1	A0A8Q3SIJ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPG5	ENST00000282041.11	TSL:1 MANE Select	c.104G>C	p.Ser35Thr	missense	Exon 2 of 44	ENSP00000282041.4	Q9HCE0-1
EPG5	ENST00000587884.2	TSL:1	n.104G>C		non_coding_transcript_exon	Exon 2 of 45	ENSP00000466990.2	K7ENK5
EPG5	ENST00000587974.1	TSL:1	n.139G>C		non_coding_transcript_exon	Exon 2 of 24

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000407

AC:

AN:

245856

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458588

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33286

American (AMR)

AF:

0.0000227

AC:

AN:

43992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25906

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.00

AC:

AN:

85850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110534

Other (OTH)

AF:

0.00

AC:

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.5

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0034

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.41

M_CAP

Benign

0.0039

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

PhyloP100

0.88

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.33

REVEL

Benign

0.085

Sift

Benign

0.28

Sift4G

Benign

0.20

Polyphen

0.0020

Vest4

0.20

MutPred

0.078

Gain of glycosylation at S34 (P = 0.051)

MVP

0.15

MPC

0.13

ClinPred

0.057

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.035

gMVP

0.067

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over