rs1008310202

chr22-31768826-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001242896.3(DEPDC5):c.376G>A(p.Ala126Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.60

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DEPDC5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.376G>A	p.Ala126Thr	missense_variant	7/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.376G>A	p.Ala126Thr	missense_variant	7/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 249026 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135092

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460606 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726624

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

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

Invitae

Aug 15, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 126 of the DEPDC5 protein (p.Ala126Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DEPDC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 466486). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;D;.;D;.;D;D;.;.;.;D;D;.;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.46	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;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.55	N;.;.;N;N;.;.;.;N;N;.;N;.;.;N;.;N;.;N;.;.;N;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.0	N;.;.;.;.;.;.;.;.;N;.;N;.;.;.;.;N;.;N;.;.;N;N;.;.;.
REVEL	Benign	0.29
Sift	Uncertain	0.016	D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;T;.;D;.;.;D;D;.;.;.
Sift4G	Uncertain	0.035	D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;T;.;D;.;.;D;T;.;.;.
Polyphen		0.059, 0.32	.;.;.;.;.;.;.;.;B;B;.;.;.;.;.;.;B;.;B;.;.;.;.;.;.;.
Vest4		0.85
MutPred		0.39		Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;.;
MVP		0.37
MPC		0.76
ClinPred		0.73	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1008310202; hg19: chr22-32164812;