rs34674177

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020964.3(EPG5):​c.5954G>A​(p.Arg1985Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,613,746 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 33 hom., cov: 32)
Exomes 𝑓: 0.0027 ( 34 hom. )

Consequence

EPG5
NM_020964.3 missense

Scores

2
16

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.28
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.002965033).
BP6
Variant 18-45876331-C-T is Benign according to our data. Variant chr18-45876331-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 466260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-45876331-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0124 (1882/152234) while in subpopulation AFR AF= 0.0368 (1527/41540). AF 95% confidence interval is 0.0352. There are 33 homozygotes in gnomad4. There are 892 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EPG5NM_020964.3 linkuse as main transcriptc.5954G>A p.Arg1985Gln missense_variant 35/44 ENST00000282041.11 NP_066015.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EPG5ENST00000282041.11 linkuse as main transcriptc.5954G>A p.Arg1985Gln missense_variant 35/441 NM_020964.3 ENSP00000282041 P4Q9HCE0-1

Frequencies

GnomAD3 genomes
AF:
0.0123
AC:
1872
AN:
152116
Hom.:
32
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0366
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.0118
Gnomad ASJ
AF:
0.00202
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.0222
Gnomad NFE
AF:
0.00187
Gnomad OTH
AF:
0.0144
GnomAD3 exomes
AF:
0.00501
AC:
1251
AN:
249564
Hom.:
20
AF XY:
0.00428
AC XY:
579
AN XY:
135396
show subpopulations
Gnomad AFR exome
AF:
0.0413
Gnomad AMR exome
AF:
0.00788
Gnomad ASJ exome
AF:
0.00238
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000523
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00228
Gnomad OTH exome
AF:
0.00693
GnomAD4 exome
AF:
0.00274
AC:
4003
AN:
1461512
Hom.:
34
Cov.:
30
AF XY:
0.00265
AC XY:
1924
AN XY:
727076
show subpopulations
Gnomad4 AFR exome
AF:
0.0394
Gnomad4 AMR exome
AF:
0.00774
Gnomad4 ASJ exome
AF:
0.00253
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000603
Gnomad4 FIN exome
AF:
0.0000562
Gnomad4 NFE exome
AF:
0.00158
Gnomad4 OTH exome
AF:
0.00548
GnomAD4 genome
AF:
0.0124
AC:
1882
AN:
152234
Hom.:
33
Cov.:
32
AF XY:
0.0120
AC XY:
892
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.0368
Gnomad4 AMR
AF:
0.0118
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.0000943
Gnomad4 NFE
AF:
0.00185
Gnomad4 OTH
AF:
0.0142
Alfa
AF:
0.00421
Hom.:
7
Bravo
AF:
0.0146
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.0376
AC:
149
ESP6500EA
AF:
0.00216
AC:
18
ExAC
AF:
0.00556
AC:
672
Asia WGS
AF:
0.00318
AC:
11
AN:
3478
EpiCase
AF:
0.00289
EpiControl
AF:
0.00279

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingGeneDxNov 11, 2020- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Vici syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Benign
0.011
T;T
Eigen
Benign
0.18
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.78
.;T
MetaRNN
Benign
0.0030
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
M;M
MutationTaster
Benign
0.93
D
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.33
N;.
REVEL
Benign
0.090
Sift
Benign
0.38
T;.
Sift4G
Benign
0.24
T;.
Polyphen
0.97
D;D
Vest4
0.18
MVP
0.43
MPC
0.22
ClinPred
0.018
T
GERP RS
5.9
Varity_R
0.11
gMVP
0.20

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34674177; hg19: chr18-43456296; API