rs765244692
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4
The NM_001242896.3(DEPDC5):c.4136C>A(p.Ser1379Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
DEPDC5
NM_001242896.3 missense
NM_001242896.3 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 5.84
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DEPDC5. . Gene score misZ 2.6501 (greater than the threshold 3.09). Trascript score misZ 3.7275 (greater than threshold 3.09). GenCC has associacion of gene with focal epilepsy, Brugada syndrome, epilepsy, familial focal, with variable foci 1, familial focal epilepsy with variable foci, autosomal dominant epilepsy with auditory features, autosomal dominant nocturnal frontal lobe epilepsy.
BP4
Computational evidence support a benign effect (MetaRNN=0.29431054).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DEPDC5 | NM_001242896.3 | c.4136C>A | p.Ser1379Tyr | missense_variant | 39/43 | ENST00000651528.2 | NP_001229825.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DEPDC5 | ENST00000651528.2 | c.4136C>A | p.Ser1379Tyr | missense_variant | 39/43 | NM_001242896.3 | ENSP00000498382 | P4 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249112Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135156
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461734Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727164
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GnomAD4 genome Cov.: 31
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31
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial focal epilepsy with variable foci Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 25, 2023 | This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 1379 of the DEPDC5 protein (p.Ser1379Tyr). This variant is present in population databases (rs765244692, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DEPDC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 466490). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;.;T;.;.;.;.;T;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;.;.;D;D;.;D;.;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;.;.;.;L;.;.;.;.;L;.;.;L;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.;.;.;.;.;N;.;.;.;N;.;.;N;.
REVEL
Benign
Sift
Benign
T;.;.;.;.;.;T;.;.;.;T;.;.;T;.
Sift4G
Benign
T;.;.;.;.;.;T;.;.;.;T;.;.;T;.
Polyphen
0.92
.;.;P;.;.;.;.;.;.;.;.;.;P;.;.
Vest4
MVP
MPC
2.5
ClinPred
T
GERP RS
Varity_R
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at