22-31765049-G-T

Variant names:

• chr22-31765049-G-T
• rs768456731
• NM_001242896.3:c.268G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 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 Likely pathogenic.

• 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]

ENSG00000285404 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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].
• BP4: Computational evidence support a benign effect (MetaRNN=0.30012286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.268G>T	p.Val90Leu	missense_variant	Exon 5 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.268G>T	p.Val90Leu	missense_variant	Exon 5 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.268G>T	p.Val90Leu	missense_variant	Exon 4 of 21			ENSP00000496158.1

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;.;.;.
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;