22-31804864-G-T

Variant names:

• chr22-31804864-G-T
• NM_001242896.3:c.1166G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001242896.3(DEPDC5):​c.1166G>T​(p.Arg389Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R389C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.27

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047274947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.1166G>T	p.Arg389Leu	missense_variant	Exon 17 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.1166G>T	p.Arg389Leu	missense_variant	Exon 17 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.1082G>T	p.Arg361Leu	missense_variant	Exon 15 of 21			ENSP00000496158.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461622 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727124

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.81
DEOGEN2	Benign	0.010	.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	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	0.047	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.;L;L;.;.;L;L;.;L;.;L;.;L;L;.;.;L;L;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.0	N;.;.;.;.;.;.;.;N;.;N;.;.;.;N;N;.;.;N;N;.;.
REVEL	Benign	0.053
Sift	Benign	1.0	T;.;.;.;.;.;.;.;T;.;T;.;.;.;T;T;.;.;T;T;.;.
Sift4G	Benign	0.69	T;.;.;.;.;.;.;.;T;.;T;.;.;.;T;T;.;.;T;T;.;.
Polyphen		0.0, 0.013	.;.;.;.;.;.;.;B;B;.;.;.;.;.;B;B;.;.;.;.;.;.
Vest4		0.28
MutPred		0.27		Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);.;Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);.;Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);.;Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);Loss of phosphorylation at S391 (P = 0.0513);.;
MVP		0.11
MPC		0.50
ClinPred		0.29	T
GERP RS		2.9
Varity_R		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-32200850;