22-31861408-C-G

Variant names:

• chr22-31861408-C-G
• NM_001242896.3:c.3305C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001242896.3(DEPDC5):​c.3305C>G​(p.Thr1102Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.48

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15949535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.3305C>G	p.Thr1102Arg	missense_variant	Exon 33 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.3305C>G	p.Thr1102Arg	missense_variant	Exon 33 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.1786+42183C>G		intron_variant	Intron 20 of 20			ENSP00000496158.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1399374 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690198

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: 0.00000185

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	0.21
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.019	.;.;.;T;.;.;T;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D;D;D;D;.;D;.;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;.;.;N;.;.;N;.;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	.;.;.;.;.;.;N;.;N
REVEL	Benign	0.17
Sift	Uncertain	0.0020	.;.;.;.;.;.;D;.;D
Sift4G	Benign	0.24	.;.;.;.;.;.;T;.;T
Vest4		0.70, 0.56
MutPred		0.25		.;.;.;Gain of MoRF binding (P = 0.015);.;.;Gain of MoRF binding (P = 0.015);.;Gain of MoRF binding (P = 0.015);
MVP		0.18
MPC		0.55
ClinPred		0.63	D
GERP RS		3.4
Varity_R		0.15

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: chr22-32257394;