rs1351408059

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001242896.3(DEPDC5):c.1412G>A(p.Gly471Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.50

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:

ENSG00000285404 (HGNC:):

ENSG00000285404 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 link	c.1412G>A	p.Gly471Asp	missense_variant	Exon 20 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.1412G>A	p.Gly471Asp	missense_variant	Exon 20 of 43		NM_001242896.3	ENSP00000498382.1		O75140-10
ENSG00000285404	ENST00000646701.1 link	c.1328G>A	p.Gly443Asp	missense_variant	Exon 18 of 21			ENSP00000496158.1		A0A2R8YF50

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249466

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135350

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial focal epilepsy with variable foci

Uncertain:1

Jan 02, 2018

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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DEPDC5-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 471 of the DEPDC5 protein (p.Gly471Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

not provided

Uncertain:1

Nov 08, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G471D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G471D variant is observed in 1/33,574 (0.003%) alleles from individuals of Latino background (Lek et al., 2016). The G471D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

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

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.88

MutationAssessor

Benign

2.0

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

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.0

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

REVEL

Uncertain

0.35

Sift

Benign

0.086

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

Sift4G

Benign

0.21

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

Polyphen

0.98, 1.0

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

Vest4

0.82

MutPred

0.28

Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);.;Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);.;Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);.;Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);Loss of catalytic residue at G471 (P = 0.0299);.;

MVP

0.28

MPC

1.4

ClinPred

0.79

GERP RS

5.6

Varity_R

0.58

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