rs371377906

chr22-31861365-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4 BP6_Very_Strong BS1

The NM_001242896.3(DEPDC5):c.3265-3C>T variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000688 in 1,551,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9428
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:6 O:1
• Conservation: PhyloP100: 5.05

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• BP6: Variant 22-31861365-C-T is Benign according to our data. Variant chr22-31861365-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 238679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31861365-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00101 (154/152246) while in subpopulation NFE AF= 0.00144 (98/68028). AF 95% confidence interval is 0.00121. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.3265-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.3265-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001242896.3	P4

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000846 AC: 132 AN: 156108 Hom.: 0 AF XY: 0.000834 AC XY: 69 AN XY: 82764

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00671

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000423

Gnomad NFE exome AF: 0.000994

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.000653 AC: 914 AN: 1399334 Hom.: 0 Cov.: 31 AF XY: 0.000713 AC XY: 492 AN XY: 690154

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.0000560

Gnomad4 ASJ exome AF: 0.00747

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.000558

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74438

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.000691

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	DEPDC5: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2020	This variant is associated with the following publications: (PMID: 29358611, 26505888) -

Epilepsy, familial focal, with variable foci 1 Benign:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 08, 2022	- -

Childhood epilepsy with centrotemporal spikes Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2018

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

DEPDC5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
Cadd	Benign	20
Dann	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.10		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: rs371377906; hg19: chr22-32257351;