22-31876263-G-C

Variant names:

• chr22-31876263-G-C
• NM_001242896.3:c.3803G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001242896.3(DEPDC5):​c.3803G>C​(p.Arg1268Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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, splice_region
• Scores: Splicing: ADA: 0.9224
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.20

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2679416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.3803G>C	p.Arg1268Pro	missense_variant, splice_region_variant	Exon 37 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.3803G>C	p.Arg1268Pro	missense_variant, splice_region_variant	Exon 37 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.1786+57038G>C		intron_variant	Intron 20 of 20			ENSP00000496158.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460908 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726736

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;.;.;.;.;T;.;.;.;.;T;.;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;.;.;D;D;.;D;.;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;.;.;.;.;L;.;.;.;.;L;.;.;L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.1	N;.;.;.;.;.;N;.;.;.;N;.;.;N;.
REVEL	Benign	0.18
Sift	Uncertain	0.010	D;.;.;.;.;.;D;.;.;.;D;.;.;D;.
Sift4G	Uncertain	0.017	D;.;.;.;.;.;D;.;.;.;D;.;.;D;.
Polyphen		0.81	.;.;P;.;.;.;.;.;.;.;.;.;P;.;.
Vest4		0.82
MVP		0.093
MPC		0.58
ClinPred		0.82	D
GERP RS		5.2
Varity_R		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Benign	0.69
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: chr22-32272249;