rs79027628
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2PP2BP4_StrongBP6BS1
The NM_001242896.3(DEPDC5):c.3311C>T(p.Ser1104Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000363 in 1,551,608 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00038 ( 0 hom. )
Consequence
DEPDC5
NM_001242896.3 missense
NM_001242896.3 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 5.05
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 Likely_benign. Variant got -6 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=0.028594702).
BP6
Variant 22-31861414-C-T is Benign according to our data. Variant chr22-31861414-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210846.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=6, not_provided=1, Benign=1}. Variant chr22-31861414-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000243 (37/152248) while in subpopulation NFE AF= 0.000412 (28/68020). AF 95% confidence interval is 0.000292. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DEPDC5 | NM_001242896.3 | c.3311C>T | p.Ser1104Leu | missense_variant | 33/43 | ENST00000651528.2 | NP_001229825.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DEPDC5 | ENST00000651528.2 | c.3311C>T | p.Ser1104Leu | missense_variant | 33/43 | NM_001242896.3 | ENSP00000498382.1 | |||
ENSG00000285404 | ENST00000646701.1 | c.1786+42189C>T | intron_variant | ENSP00000496158.1 |
Frequencies
GnomAD3 genomes AF: 0.000243 AC: 37AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000198 AC: 31AN: 156402Hom.: 0 AF XY: 0.000217 AC XY: 18AN XY: 82898
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GnomAD4 exome AF: 0.000377 AC: 527AN: 1399360Hom.: 0 Cov.: 31 AF XY: 0.000381 AC XY: 263AN XY: 690186
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GnomAD4 genome AF: 0.000243 AC: 37AN: 152248Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74440
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Epilepsy, familial focal, with variable foci 1 Uncertain:3Benign:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 19, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This c.3311C>T (p.S1104L) variant has been previously reported in patients with FFEVF1 or paroxysmal kinesigenic dyskinesia [PMID 23542697, 29356177], however, another study found this variant lacks strong segregation support [PMID 28717674] - |
Likely benign, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2020 | This variant is associated with the following publications: (PMID: 31639411, 31594065, 31139143, 30093711, 28717674, 23542697, 29356177, 25366275, 27683934) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 07, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 19, 2015 | - - |
Familial focal epilepsy with variable foci Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1104 of the DEPDC5 protein (p.Ser1104Leu). This variant is present in population databases (rs79027628, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of DEPDC5-related conditions (PMID: 23542697, 29356177, 31139143, 31594065). ClinVar contains an entry for this variant (Variation ID: 210846). 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. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 10, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
DEPDC5-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 22, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;.;.;T;.;.;T;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;.;D;.;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;.;.;L;.;.;L;.;L
PrimateAI
Uncertain
T
PROVEAN
Benign
.;.;.;.;.;.;N;.;N
REVEL
Benign
Sift
Uncertain
.;.;.;.;.;.;D;.;D
Sift4G
Benign
.;.;.;.;.;.;T;.;T
Vest4
0.64, 0.81
MVP
0.23
MPC
0.38
ClinPred
T
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at