rs146449468

chr22-31906059-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001242896.3(DEPDC5):c.4512C>T(p.His1504=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,614,118 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 19 hom., cov: 32)

Exomes 𝑓: 0.019 ( 303 hom. )

Consequence

DEPDC5
NM_001242896.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.975

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005276859).

BP6

Variant 22-31906059-C-T is Benign according to our data. Variant chr22-31906059-C-T is described in ClinVar as [Benign]. Clinvar id is 238682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31906059-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.975 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0142 (2164/152310) while in subpopulation SAS AF= 0.0209 (101/4822). AF 95% confidence interval is 0.0183. There are 19 homozygotes in gnomad4. There are 1106 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3 linkuse as main transcript	c.4512C>T	p.His1504=	synonymous_variant	42/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2 linkuse as main transcript	c.4512C>T	p.His1504=	synonymous_variant	42/43		NM_001242896.3	P4	O75140-10

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2162

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00328

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0159

Gnomad ASJ

AF:

0.00806

Gnomad EAS

AF:

0.00250

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.0250

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0191

Gnomad OTH

AF:

0.0239

GnomAD3 exomes

AF:

0.0177

AC:

4425

AN:

249444

Hom.:

AF XY:

0.0186

AC XY:

2519

AN XY:

135346

show subpopulations

Gnomad AFR exome

AF:

0.00220

Gnomad AMR exome

AF:

0.0140

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.00267

Gnomad SAS exome

AF:

0.0264

Gnomad FIN exome

AF:

0.0239

Gnomad NFE exome

AF:

0.0203

Gnomad OTH exome

AF:

0.0220

GnomAD4 exome

AF:

0.0192

AC:

28084

AN:

1461808

Hom.:

303

Cov.:

AF XY:

0.0195

AC XY:

14202

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.00230

Gnomad4 AMR exome

AF:

0.0139

Gnomad4 ASJ exome

AF:

0.00949

Gnomad4 EAS exome

AF:

0.00214

Gnomad4 SAS exome

AF:

0.0254

Gnomad4 FIN exome

AF:

0.0247

Gnomad4 NFE exome

AF:

0.0201

Gnomad4 OTH exome

AF:

0.0174

GnomAD4 genome

AF:

0.0142

AC:

2164

AN:

152310

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1106

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00327

Gnomad4 AMR

AF:

0.0159

Gnomad4 ASJ

AF:

0.00806

Gnomad4 EAS

AF:

0.00251

Gnomad4 SAS

AF:

0.0209

Gnomad4 FIN

AF:

0.0250

Gnomad4 NFE

AF:

0.0191

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.0195

Hom.:

Bravo

AF:

0.0139

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0179

AC:

ESP6500AA

AF:

0.00302

AC:

ESP6500EA

AF:

0.0211

AC:

175

ExAC

AF:

0.0172

AC:

2084

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0216

EpiControl

AF:

0.0218

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2016

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

Cadd

Benign

0.55

Dann

Benign

0.95

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.78

MutationTaster

Benign

1.0

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

PROVEAN

Benign

0.31

REVEL

Benign

0.16

Sift

Benign

0.47

Sift4G

Pathogenic

0.0

Vest4

0.20

ClinPred

0.024

GERP RS

-8.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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