rs118001924

chr22-31843753-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001242896.3(DEPDC5):c.2742G>A(p.Glu914=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,614,024 control chromosomes in the GnomAD database, including 191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (19 hom., cov: 32)
  • Exomes 𝑓: 0.014 (172 hom.)
• Consequence: DEPDC5 NM_001242896.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.08

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 22-31843753-G-A is Benign according to our data. Variant chr22-31843753-G-A is described in ClinVar as [Benign]. Clinvar id is 238677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31843753-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0116 (1773/152240) while in subpopulation AMR AF= 0.0189 (289/15290). AF 95% confidence interval is 0.0171. There are 19 homozygotes in gnomad4. There are 858 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.2742G>A	p.Glu914=	synonymous_variant	29/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.2742G>A	p.Glu914=	synonymous_variant	29/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1773 AN: 152122 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00680

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0119 AC: 2982 AN: 249572 Hom.: 27 AF XY: 0.0125 AC XY: 1696 AN XY: 135402

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00773

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0122

Gnomad FIN exome AF: 0.00881

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0135 AC: 19805 AN: 1461784 Hom.: 172 Cov.: 31 AF XY: 0.0137 AC XY: 9987 AN XY: 727184

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.00760

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.00973

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.0133

GnomAD4 genome AF: 0.0116 AC: 1773 AN: 152240 Hom.: 19 Cov.: 32 AF XY: 0.0115 AC XY: 858 AN XY: 74420

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.0189

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.00680

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0153 Hom.: 29

Bravo AF: 0.0115

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0176

EpiControl AF: 0.0186

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

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- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 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 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	7.6
Dann	Benign	0.47

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: rs118001924; hg19: chr22-32239739; COSMIC: COSV56705363; COSMIC: COSV56705363;