rs79070552

chr22-31804175-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001242896.3(DEPDC5):c.1095T>C(p.Asp365=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,613,836 control chromosomes in the GnomAD database, including 375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (60 hom., cov: 32)
  • Exomes 𝑓: 0.020 (315 hom.)
• Consequence: DEPDC5 NM_001242896.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.290

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=-0.6).
• BP6: Variant 22-31804175-T-C is Benign according to our data. Variant chr22-31804175-T-C is described in ClinVar as [Benign]. Clinvar id is 257657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31804175-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0251 (3817/152176) while in subpopulation AFR AF= 0.0413 (1716/41520). AF 95% confidence interval is 0.0397. There are 60 homozygotes in gnomad4. There are 1887 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.1095T>C	p.Asp365=	synonymous_variant	16/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.1095T>C	p.Asp365=	synonymous_variant	16/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3812 AN: 152058 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0414

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00386

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0246

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0190

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0201 AC: 5021 AN: 249492 Hom.: 51 AF XY: 0.0201 AC XY: 2722 AN XY: 135352

Gnomad AFR exome AF: 0.0413

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.00993

Gnomad EAS exome AF: 0.00406

Gnomad SAS exome AF: 0.0232

Gnomad FIN exome AF: 0.0242

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0239

GnomAD4 exome AF: 0.0197 AC: 28817 AN: 1461660 Hom.: 315 Cov.: 30 AF XY: 0.0199 AC XY: 14439 AN XY: 727146

Gnomad4 AFR exome AF: 0.0423

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.00815

Gnomad4 EAS exome AF: 0.00280

Gnomad4 SAS exome AF: 0.0232

Gnomad4 FIN exome AF: 0.0248

Gnomad4 NFE exome AF: 0.0195

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.0251 AC: 3817 AN: 152176 Hom.: 60 Cov.: 32 AF XY: 0.0254 AC XY: 1887 AN XY: 74404

Gnomad4 AFR AF: 0.0413

Gnomad4 AMR AF: 0.0200

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00386

Gnomad4 SAS AF: 0.0216

Gnomad4 FIN AF: 0.0246

Gnomad4 NFE AF: 0.0190

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0217 Hom.: 21

Bravo AF: 0.0263

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.0212

EpiControl AF: 0.0215

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	May 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 24, 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

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.8
Dann	Benign	0.49

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: rs79070552; hg19: chr22-32200161; COSMIC: COSV56707603; COSMIC: COSV56707603;