Genetic Variant EPG5:p.Gln336Leu (chr18-45954395-T-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_020964.3(EPG5):c.1007A>T(p.Gln336Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000693 in 1,442,632 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. 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. Q336R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EPG5
NM_020964.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.06

Publications

0 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: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr18-45954395-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 192333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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
EPG5	NM_020964.3	MANE Select	c.1007A>T	p.Gln336Leu	missense splice_region	Exon 2 of 44	NP_066015.2
EPG5	NM_001410859.1		c.1007A>T	p.Gln336Leu	missense splice_region	Exon 2 of 44	NP_001397788.1
EPG5	NM_001410858.1		c.1007A>T	p.Gln336Leu	missense splice_region	Exon 2 of 44	NP_001397787.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPG5	ENST00000282041.11	TSL:1 MANE Select	c.1007A>T	p.Gln336Leu	missense splice_region	Exon 2 of 44	ENSP00000282041.4
EPG5	ENST00000587884.2	TSL:1	n.1007A>T		splice_region non_coding_transcript_exon	Exon 2 of 45	ENSP00000466990.2
EPG5	ENST00000587974.1	TSL:1	n.1042A>T		splice_region non_coding_transcript_exon	Exon 2 of 24

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716704

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32694

American (AMR)

AF:

0.00

AC:

AN:

41608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24374

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00

AC:

AN:

82766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103900

Other (OTH)

AF:

0.00

AC:

AN:

59484

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.0

PhyloP100

7.1

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.59

Sift

Benign

0.049

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.56

MutPred

0.47

Gain of sheet (P = 0.0011)

MVP

0.73

MPC

0.56

ClinPred

0.98

GERP RS

6.1

Varity_R

0.27

gMVP

0.38

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.88

Position offset: -1

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