rs373578854

Positions:

• chr22-31765014-G-A
• chr22-31765014-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001242896.3(DEPDC5):​c.233G>A​(p.Arg78Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.17

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]

ENSG00000285404 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DEPDC5. . Gene score misZ 2.6501 (greater than the threshold 3.09). Trascript score misZ 3.7275 (greater than threshold 3.09). GenCC has associacion of gene with focal epilepsy, Brugada syndrome, epilepsy, familial focal, with variable foci 1, familial focal epilepsy with variable foci, autosomal dominant epilepsy with auditory features, autosomal dominant nocturnal frontal lobe epilepsy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08122468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.233G>A	p.Arg78Gln	missense_variant	5/43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.233G>A	p.Arg78Gln	missense_variant	5/43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.233G>A	p.Arg78Gln	missense_variant	4/21			ENSP00000496158.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249530 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135380

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461812 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial focal epilepsy with variable foci Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.016	.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;.;.;D;D;.;.;.;D;D;.;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.081	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N;.;.;N;N;.;.;.;N;N;.;N;.;N;.;N;.;N;.;.;N;N;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.53	N;.;.;.;.;.;.;.;.;N;.;N;.;.;.;N;.;N;.;.;N;N;.;.;.
REVEL	Benign	0.096
Sift	Benign	1.0	T;.;.;.;.;.;.;.;.;T;.;T;.;.;.;T;.;T;.;.;T;T;.;.;.
Sift4G	Benign	0.78	T;.;.;.;.;.;.;.;.;T;.;T;.;.;.;T;.;T;.;.;T;T;.;.;.
Polyphen		0.0060, 0.071	.;.;.;.;.;.;.;.;B;B;.;.;.;.;.;B;.;B;.;.;.;.;.;.;.
Vest4		0.47
MutPred		0.38		Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);.;Loss of catalytic residue at R78 (P = 0.1288);
MVP		0.31
MPC		0.53
ClinPred		0.18	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18

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: rs373578854; hg19: chr22-32161000;