18-45955298-C-T

Position:

chr18-45955298-C-T

Variant summary

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

The ENST00000282041.11(EPG5):c.104G>A(p.Ser35Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000945 in 1,610,888 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S35G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0052 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 9 hom. )

Consequence

EPG5
ENST00000282041.11 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.880

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 links:

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=0.0029449463).

BP6

Variant 18-45955298-C-T is Benign according to our data. Variant chr18-45955298-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 466235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-45955298-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00523 (797/152302) while in subpopulation AFR AF= 0.0179 (742/41568). AF 95% confidence interval is 0.0168. There are 6 homozygotes in gnomad4. There are 389 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPG5	NM_020964.3 linkuse as main transcript	c.104G>A	p.Ser35Asn	missense_variant	2/44	ENST00000282041.11	NP_066015.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPG5	ENST00000282041.11 linkuse as main transcript	c.104G>A	p.Ser35Asn	missense_variant	2/44	1	NM_020964.3	ENSP00000282041	P4	Q9HCE0-1

Frequencies

GnomAD3 genomes

AF:

0.00523

AC:

796

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00116

AC:

286

AN:

245856

Hom.:

AF XY:

0.000899

AC XY:

120

AN XY:

133522

show subpopulations

Gnomad AFR exome

AF:

0.0174

Gnomad AMR exome

AF:

0.000447

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.000498

AC:

726

AN:

1458586

Hom.:

Cov.:

AF XY:

0.000426

AC XY:

309

AN XY:

725564

show subpopulations

Gnomad4 AFR exome

AF:

0.0177

Gnomad4 AMR exome

AF:

0.000818

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00523

AC:

797

AN:

152302

Hom.:

Cov.:

AF XY:

0.00522

AC XY:

389

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0179

Gnomad4 AMR

AF:

0.00262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.000945

Hom.:

Bravo

AF:

0.00597

ESP6500AA

AF:

0.0158

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.000866

AC:

AN:

3478

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 submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Vici syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

9.6

DANN

Benign

0.60

DEOGEN2

Benign

0.0037

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.25

.;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

0.020

N;.

REVEL

Benign

0.091

Sift

Benign

0.33

T;.

Sift4G

Benign

0.41

T;.

Polyphen

0.0

B;B

Vest4

0.15

MVP

0.15

MPC

0.14

ClinPred

0.0044

GERP RS

4.8

Varity_R

0.029

gMVP

0.052

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over