rs5998135

Positions:

• chr22-31809646-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001242896.3(DEPDC5):​c.1323A>C​(p.Thr441=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,613,484 control chromosomes in the GnomAD database, including 8,690 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (987 hom., cov: 32)
  • Exomes 𝑓: 0.099 (7703 hom.)
• Consequence: DEPDC5 NM_001242896.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.01390
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.926

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-31809646-A-C is Benign according to our data. Variant chr22-31809646-A-C is described in ClinVar as [Benign]. Clinvar id is 257658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.1323A>C	p.Thr441=	splice_region_variant, synonymous_variant	19/43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.1323A>C	p.Thr441=	splice_region_variant, synonymous_variant	19/43		NM_001242896.3	ENSP00000498382	P4

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16803 AN: 152118 Hom.: 984 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.149

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0367

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.109

GnomAD3 exomes AF: 0.106 AC: 26358 AN: 249318 Hom.: 1651 AF XY: 0.101 AC XY: 13613 AN XY: 135274

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.0993

Gnomad EAS exome AF: 0.0392

Gnomad SAS exome AF: 0.0505

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0991 AC: 144829 AN: 1461248 Hom.: 7703 Cov.: 31 AF XY: 0.0971 AC XY: 70603 AN XY: 726948

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.0311

Gnomad4 SAS exome AF: 0.0510

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.0954

GnomAD4 genome AF: 0.111 AC: 16832 AN: 152236 Hom.: 987 Cov.: 32 AF XY: 0.109 AC XY: 8138 AN XY: 74432

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.0368

Gnomad4 SAS AF: 0.0439

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.108

Alfa AF: 0.102 Hom.: 1409

Bravo AF: 0.115

Asia WGS AF: 0.0720 AC: 251 AN: 3478

EpiCase AF: 0.0979

EpiControl AF: 0.106

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 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

Jan 08, 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.3
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.36
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: rs5998135; hg19: chr22-32205632; COSMIC: COSV56697481; COSMIC: COSV56697481;