22-31765049-G-T

Position:

• chr22-31765049-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PM5 PP2 BP4

The NM_001242896.3(DEPDC5):​c.268G>T​(p.Val90Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V90I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.46

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-31765049-G-A is described in Lovd as [Likely_pathogenic].
• 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=0.30012286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.268G>T	p.Val90Leu	missense_variant	5/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.268G>T	p.Val90Leu	missense_variant	5/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460566 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726636

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;.;.;D;D;.;.;.;D;D;.;D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.30	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	-0.92	T
MutationAssessor	Benign	1.9	L;.;.;L;L;.;.;.;L;L;.;L;.;L;.;L;.;L;.;.;L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.5	N;.;.;.;.;.;.;.;.;N;.;N;.;.;.;D;.;N;.;.;N;N;.;.;.
REVEL	Benign	0.10
Sift	Uncertain	0.0080	D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;D;.;D;.;.;D;D;.;.;.
Sift4G	Uncertain	0.010	D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;D;.;D;.;.;D;D;.;.;.
Polyphen		0.93, 0.91	.;.;.;.;.;.;.;.;P;P;.;.;.;.;.;P;.;P;.;.;.;.;.;.;.
Vest4		0.33
MutPred		0.45		Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);Loss of ubiquitination at K93 (P = 0.0982);.;Loss of ubiquitination at K93 (P = 0.0982);
MVP		0.35
MPC		0.39
ClinPred		0.89	D
GERP RS		4.1
Varity_R		0.24

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: rs768456731; hg19: chr22-32161035;