rs528786894

Positions:

chr22-31861408-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001242896.3(DEPDC5):c.3305C>T(p.Thr1102Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,551,644 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.48

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DEPDC5. . Gene score misZ 2.6501 (greater than the threshold 3.09). Trascript score misZ 3.7275 (greater than threshold 3.09). GenCC has associacion of gene with focal epilepsy, Brugada syndrome, epilepsy, familial focal, with variable foci 1, familial focal epilepsy with variable foci, autosomal dominant epilepsy with auditory features, autosomal dominant nocturnal frontal lobe epilepsy.

BP4

Computational evidence support a benign effect (MetaRNN=0.082802385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 linkuse as main transcript	c.3305C>T	p.Thr1102Ile	missense_variant	33/43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2 linkuse as main transcript	c.3305C>T	p.Thr1102Ile	missense_variant	33/43		NM_001242896.3	ENSP00000498382	P4	O75140-10

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399374

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

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

AF:

0.00000657

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epilepsy, familial focal, with variable foci 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 19, 2023

The DEPDC5 c.3305C>T (p.Thr1102Ile) missense variant has not, to our knowledge, been reported in the peer-reviewed literature. This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.3305C>T (p.Thr1102Ile) variant is classified as a variant of uncertain significance for DEPDC5-related epilepsy. -

Familial focal epilepsy with variable foci

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2024

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1102 of the DEPDC5 protein (p.Thr1102Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DEPDC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 407348). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.015

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

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.075

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.87

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

M_CAP

Benign

0.020

MetaRNN

Benign

0.083

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.49

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

REVEL

Benign

0.022

Sift

Uncertain

0.0020

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

Sift4G

Benign

0.17

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

Vest4

0.67, 0.60

MutPred

0.22

.;.;.;Loss of phosphorylation at T1102 (P = 0.0155);.;.;Loss of phosphorylation at T1102 (P = 0.0155);.;Loss of phosphorylation at T1102 (P = 0.0155);

MVP

0.10

MPC

0.49

ClinPred

0.64

GERP RS

3.4

Varity_R

0.089

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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