22-31876263-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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 š‘“: 6.8e-7 ( 0 hom. )

Consequence

DEPDC5
NM_001242896.3 missense, splice_region

Scores

9
10
Splicing: ADA: 0.9224
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.20
Variant links:
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]

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ACMG classification

Classification made for transcript

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
DEPDC5NM_001242896.3 linkc.3803G>C p.Arg1268Pro missense_variant, splice_region_variant Exon 37 of 43 ENST00000651528.2 NP_001229825.1 O75140-10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DEPDC5ENST00000651528.2 linkc.3803G>C p.Arg1268Pro missense_variant, splice_region_variant Exon 37 of 43 NM_001242896.3 ENSP00000498382.1 O75140-10
ENSG00000285404ENST00000646701.1 linkc.1786+57038G>C intron_variant Intron 20 of 20 ENSP00000496158.1 A0A2R8YF50

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
show subpopulations
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; API