rs535630975

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM2PP2BP4_StrongBP6_Very_StrongBS1

The NM_001242896.3(DEPDC5):c.138T>A(p.Asp46Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000057 in 1,613,974 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. D46V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 1 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.93

Variant links:

Genes affected

DEPDC5 (HGNC:18423): (DEP domain containing 5, GATOR1 subcomplex subunit) This gene encodes a member of the IML1 family of proteins involved in G-protein signaling pathways. The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth by sensing the availability of nutrients. The protein encoded by this gene is a component of the GATOR1 (GAP activity toward Rags) complex which inhibits the amino acid-sensing branch of the mTORC1 pathway. Mutations in this gene are associated with autosomal dominant familial focal epilepsy with variable foci. A single nucleotide polymorphism in an intron of this gene has been associated with an increased risk of hepatocellular carcinoma in individuals with chronic hepatitis C virus infection. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

DEPDC5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, DEPDC5

BP4

Computational evidence support a benign effect (MetaRNN=0.019622713).

BP6

Variant 22-31758625-T-A is Benign according to our data. Variant chr22-31758625-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 466452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000394 (6/152272) while in subpopulation SAS AF= 0.00104 (5/4828). AF 95% confidence interval is 0.000408. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3 linkuse as main transcript	c.138T>A	p.Asp46Glu	missense_variant	3/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2 linkuse as main transcript	c.138T>A	p.Asp46Glu	missense_variant	3/43		NM_001242896.3	P4	O75140-10

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000140

AC:

AN:

249548

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

135390

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 SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000893

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial focal epilepsy with variable foci

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 02, 2018

- -

DEPDC5-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.32

Cadd

Benign

Dann

Benign

0.97

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;D;D;D;.;.;D;D;.;.;.;D;D;.;D;D;D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.020

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.;.;L;L;.;.;.;L;L;.;L;.;L;.;L;.;L;.;.;L;L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;N

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.7

N;.;.;.;.;.;.;.;.;N;.;N;.;.;.;N;.;N;.;.;N;N;.;.;.

REVEL

Benign

0.20

Sift

Benign

0.43

T;.;.;.;.;.;.;.;.;T;.;T;.;.;.;T;.;T;.;.;T;T;.;.;.

Sift4G

Benign

0.49

T;.;.;.;.;.;.;.;.;T;.;T;.;.;.;T;.;T;.;.;T;T;.;.;.

Polyphen

0.038, 0.40

.;.;.;.;.;.;.;.;B;B;.;.;.;.;.;B;.;B;.;.;.;.;.;.;.

Vest4

0.71

MutPred

0.33

Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);Loss of phosphorylation at Y48 (P = 0.0892);.;Loss of phosphorylation at Y48 (P = 0.0892);

MVP

0.23

MPC

0.83

ClinPred

0.062

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

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