rs16989528

chr22-31821553-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001242896.3(DEPDC5):c.1922C>T(p.Ala641Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,614,110 control chromosomes in the GnomAD database, including 1,125 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A641T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (99 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1026 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.08

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DEPDC5
• BP4: Computational evidence support a benign effect (MetaRNN=0.001611352).
• BP6: Variant 22-31821553-C-T is Benign according to our data. Variant chr22-31821553-C-T is described in ClinVar as [Benign]. Clinvar id is 257659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31821553-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.1922C>T	p.Ala641Val	missense_variant	23/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.1922C>T	p.Ala641Val	missense_variant	23/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4342 AN: 152180 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.0225

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.0855

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0348 AC: 8664 AN: 249060 Hom.: 224 AF XY: 0.0372 AC XY: 5025 AN XY: 135166

Gnomad AFR exome AF: 0.00555

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0236

Gnomad EAS exome AF: 0.0201

Gnomad SAS exome AF: 0.0537

Gnomad FIN exome AF: 0.0802

Gnomad NFE exome AF: 0.0346

Gnomad OTH exome AF: 0.0322

GnomAD4 exome AF: 0.0344 AC: 50347 AN: 1461812 Hom.: 1026 Cov.: 31 AF XY: 0.0352 AC XY: 25585 AN XY: 727196

Gnomad4 AFR exome AF: 0.00499

Gnomad4 AMR exome AF: 0.0155

Gnomad4 ASJ exome AF: 0.0257

Gnomad4 EAS exome AF: 0.0264

Gnomad4 SAS exome AF: 0.0562

Gnomad4 FIN exome AF: 0.0760

Gnomad4 NFE exome AF: 0.0330

Gnomad4 OTH exome AF: 0.0336

GnomAD4 genome AF: 0.0285 AC: 4341 AN: 152298 Hom.: 99 Cov.: 32 AF XY: 0.0320 AC XY: 2384 AN XY: 74460

Gnomad4 AFR AF: 0.00520

Gnomad4 AMR AF: 0.0221

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.0224

Gnomad4 SAS AF: 0.0634

Gnomad4 FIN AF: 0.0855

Gnomad4 NFE AF: 0.0342

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0312 Hom.: 159

Bravo AF: 0.0215

TwinsUK AF: 0.0272 AC: 101

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00541 AC: 22

ESP6500EA AF: 0.0295 AC: 247

ExAC AF: 0.0357 AC: 4312

Asia WGS AF: 0.0360 AC: 128 AN: 3478

EpiCase AF: 0.0356

EpiControl AF: 0.0326

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 26, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -

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

May 26, 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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;.;D;D;.;D;.;D;D
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
Polyphen		0.061, 0.036	.;.;B;.;B;.;.;.;B;.;B;.;.
Vest4		0.093, 0.17, 0.11, 0.063, 0.10
MPC		0.40
ClinPred		0.011	T
GERP RS		0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036

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

Other links and lift over

dbSNP: rs16989528; hg19: chr22-32217539; COSMIC: COSV56700799; COSMIC: COSV56700799;