22-31783965-T-C

Variant names:

• chr22-31783965-T-C
• NM_001242896.3:c.542T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001242896.3(DEPDC5):​c.542T>C​(p.Met181Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 6.8e-7 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.99

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.542T>C	p.Met181Thr	missense_variant	Exon 9 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.542T>C	p.Met181Thr	missense_variant	Exon 9 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.458T>C	p.Met153Thr	missense_variant	Exon 7 of 21			ENSP00000496158.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461348 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726968

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;.;.;D;D;.;.;.;D;D;.;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.81	D;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	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.5	M;.;.;M;M;.;.;.;M;M;.;M;.;M;.;M;.;M;.;.;M;M;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.5	D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;D;.;D;.;.;D;D;.;.;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;D;.;D;.;.;D;D;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;D;.;D;.;.;D;D;.;.;.
Polyphen		0.77, 0.80	.;.;.;.;.;.;.;.;P;P;.;.;.;.;.;P;.;P;.;.;.;.;.;.;.
Vest4		0.92
MutPred		0.69		Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);.;Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);.;Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);.;Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);Gain of catalytic residue at M181 (P = 0.0408);.;.;
MVP		0.43
MPC		0.91
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.65

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: chr22-32179951;