22-31754971-G-T

Position:

• chr22-31754971-G-T

Variant summary

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

The NM_001242896.3(DEPDC5):​c.50G>T​(p.Gly17Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.50G>T	p.Gly17Val	missense_variant	2/43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.50G>T	p.Gly17Val	missense_variant	2/43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.50G>T	p.Gly17Val	missense_variant	1/21			ENSP00000496158.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;.;.;D;D;.;.;.;D;D;.;D;D;D
M_CAP	Benign	0.066	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;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L;.;.;L;L;.;.;.;L;L;.;L;.;L;.;L;.;L;.;.;L;L;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;.;.;.;.;.;D;.;.;N;.;N;.;.;.;D;.;N;.;.;N;N;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.013	D;.;.;.;.;.;D;.;.;D;.;D;.;.;.;D;.;D;.;.;D;D;.;.
Sift4G	Uncertain	0.0060	D;.;.;.;.;.;D;.;.;D;.;D;.;.;.;D;.;D;.;.;D;D;.;.
Polyphen		0.81, 1.0	.;.;.;.;.;.;.;.;P;D;.;.;.;.;.;P;.;D;.;.;.;.;.;.
Vest4		0.84
MutPred		0.38		Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);Loss of disorder (P = 0.0274);
MVP		0.20
MPC		1.4
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62

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: chr22-32150957;