rs16989495

chr22-31798595-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001242896.3(DEPDC5):c.885A>G(p.Gln295=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 1,610,742 control chromosomes in the GnomAD database, including 1,124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (109 hom., cov: 31)
  • Exomes 𝑓: 0.035 (1015 hom.)
• Consequence: DEPDC5 NM_001242896.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0840

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 22-31798595-A-G is Benign according to our data. Variant chr22-31798595-A-G is described in ClinVar as [Benign]. Clinvar id is 257663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31798595-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.084 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.885A>G	p.Gln295=	synonymous_variant	14/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.885A>G	p.Gln295=	synonymous_variant	14/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5127 AN: 152160 Hom.: 108 Cov.: 31

Gnomad AFR AF: 0.0241

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0233

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.0633

Gnomad FIN AF: 0.0834

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0358 AC: 8907 AN: 249028 Hom.: 225 AF XY: 0.0378 AC XY: 5104 AN XY: 135080

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0236

Gnomad EAS exome AF: 0.0203

Gnomad SAS exome AF: 0.0535

Gnomad FIN exome AF: 0.0768

Gnomad NFE exome AF: 0.0343

Gnomad OTH exome AF: 0.0318

GnomAD4 exome AF: 0.0346 AC: 50446 AN: 1458464 Hom.: 1015 Cov.: 31 AF XY: 0.0353 AC XY: 25607 AN XY: 725628

Gnomad4 AFR exome AF: 0.0256

Gnomad4 AMR exome AF: 0.0164

Gnomad4 ASJ exome AF: 0.0254

Gnomad4 EAS exome AF: 0.0263

Gnomad4 SAS exome AF: 0.0560

Gnomad4 FIN exome AF: 0.0722

Gnomad4 NFE exome AF: 0.0327

Gnomad4 OTH exome AF: 0.0343

GnomAD4 genome AF: 0.0337 AC: 5126 AN: 152278 Hom.: 109 Cov.: 31 AF XY: 0.0368 AC XY: 2743 AN XY: 74448

Gnomad4 AFR AF: 0.0241

Gnomad4 AMR AF: 0.0232

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.0226

Gnomad4 SAS AF: 0.0634

Gnomad4 FIN AF: 0.0834

Gnomad4 NFE AF: 0.0342

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0320 Hom.: 122

Bravo AF: 0.0275

Asia WGS AF: 0.0340 AC: 120 AN: 3478

EpiCase AF: 0.0358

EpiControl AF: 0.0322

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Mar 02, 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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	6.3
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs16989495; hg19: chr22-32194581; COSMIC: COSV56700757;