22-31810581-A-T

Variant names:

• chr22-31810581-A-T
• NM_001242896.3:c.1385A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001242896.3(DEPDC5):​c.1385A>T​(p.Tyr462Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.86

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.1385A>T	p.Tyr462Phe	missense_variant	Exon 20 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.1385A>T	p.Tyr462Phe	missense_variant	Exon 20 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.1301A>T	p.Tyr434Phe	missense_variant	Exon 18 of 21			ENSP00000496158.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

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: 0.00000540

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	0.23
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	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	0.045	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	2.0	M;.;.;M;M;.;.;M;M;.;M;.;M;.;M;M;.;.;M;M;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.3	D;.;.;.;.;.;.;.;D;.;D;.;.;.;D;D;.;.;D;D;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;D;.;D;.;.;.;T;T;.;.;D;T;.;.
Sift4G	Benign	0.091	T;.;.;.;.;.;.;.;D;.;D;.;.;.;T;D;.;.;D;D;.;.
Polyphen		0.24, 0.94	.;.;.;.;.;.;.;B;P;.;.;.;.;.;B;P;.;.;.;.;.;.
Vest4		0.64
MutPred		0.56		Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);.;Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);.;Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);.;Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);Loss of phosphorylation at Y462 (P = 0.0103);.;
MVP		0.46
MPC		0.92
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr22-32206567;