rs375702574

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001242896.3(DEPDC5):c.3366C>A(p.Asp1122Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000419 in 1,431,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D1122D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.07

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

epilepsy, familial focal, with variable foci 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Illumina, G2P
focal epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant epilepsy with auditory features
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant nocturnal frontal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial focal epilepsy with variable foci
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DEPDC5 links:

ENSG00000285404 (HGNC:):

ENSG00000285404 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08289036).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 link	c.3366C>A	p.Asp1122Glu	missense_variant	Exon 34 of 43	ENST00000651528.2	NP_001229825.1	O75140-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2 link	c.3366C>A	p.Asp1122Glu	missense_variant	Exon 34 of 43		NM_001242896.3	ENSP00000498382.1		O75140-10
ENSG00000285404	ENST00000646701.1 link	c.1786+51400C>A		intron_variant	Intron 20 of 20			ENSP00000496158.1		A0A2R8YF50

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000178

AC:

AN:

224514

AF XY:

0.0000327

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000419

AC:

AN:

1431562

Hom.:

Cov.:

AF XY:

0.00000843

AC XY:

AN XY:

711450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31984

American (AMR)

AF:

0.00

AC:

AN:

38814

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25026

East Asian (EAS)

AF:

0.00

AC:

AN:

37734

South Asian (SAS)

AF:

0.0000741

AC:

AN:

80962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099174

Other (OTH)

AF:

0.00

AC:

AN:

59128

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.:

ExAC

AF:

0.0000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial focal epilepsy with variable foci

Uncertain:1

Dec 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with DEPDC5-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1122 of the DEPDC5 protein (p.Asp1122Glu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.12

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

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

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.85

T;D;T;T;D;D;.;.;T;D;.;T;.;D;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.083

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

.;.;.;.;.;M;.;.;.;.;M;.;.;M;.

PhyloP100

-1.1

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.70

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

REVEL

Benign

0.10

Sift

Benign

0.11

T;.;.;.;.;.;T;.;.;.;D;.;.;D;.

Sift4G

Benign

1.0

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

Polyphen

0.60

.;.;P;.;.;.;.;.;.;.;.;.;P;.;.

Vest4

0.26

MVP

0.17

MPC

0.39

ClinPred

0.11

GERP RS

-1.4

Varity_R

0.029

Mutation Taster

=94/6

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over