chr22-31797646-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001242896.3(DEPDC5):​c.814G>A​(p.Val272Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,614,010 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 31)
Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

1
6
11

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.89
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0087249875).
BP6
Variant 22-31797646-G-A is Benign according to our data. Variant chr22-31797646-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 414466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31797646-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00156 (237/152188) while in subpopulation NFE AF= 0.000897 (61/68004). AF 95% confidence interval is 0.000716. There are 2 homozygotes in gnomad4. There are 156 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DEPDC5NM_001242896.3 linkc.814G>A p.Val272Ile missense_variant 13/43 ENST00000651528.2 NP_001229825.1 O75140-10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DEPDC5ENST00000651528.2 linkc.814G>A p.Val272Ile missense_variant 13/43 NM_001242896.3 ENSP00000498382.1 O75140-10
ENSG00000285404ENST00000646701.1 linkc.730G>A p.Val244Ile missense_variant 11/21 ENSP00000496158.1 A0A2R8YF50

Frequencies

GnomAD3 genomes
AF:
0.00156
AC:
237
AN:
152070
Hom.:
2
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0150
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000897
Gnomad OTH
AF:
0.00144
GnomAD3 exomes
AF:
0.00221
AC:
551
AN:
249096
Hom.:
2
AF XY:
0.00206
AC XY:
278
AN XY:
135138
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00199
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.0150
Gnomad NFE exome
AF:
0.00168
Gnomad OTH exome
AF:
0.00248
GnomAD4 exome
AF:
0.00119
AC:
1738
AN:
1461822
Hom.:
4
Cov.:
30
AF XY:
0.00112
AC XY:
818
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00195
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.0145
Gnomad4 NFE exome
AF:
0.000752
Gnomad4 OTH exome
AF:
0.00109
GnomAD4 genome
AF:
0.00156
AC:
237
AN:
152188
Hom.:
2
Cov.:
31
AF XY:
0.00210
AC XY:
156
AN XY:
74408
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0150
Gnomad4 NFE
AF:
0.000897
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000772
Hom.:
0
Bravo
AF:
0.000476
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000969
AC:
8
ExAC
AF:
0.00254
AC:
307
EpiCase
AF:
0.000436
EpiControl
AF:
0.000830

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Likely benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxApr 15, 2021- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 01, 2017- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Familial focal epilepsy with variable foci Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 20, 2025- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.18
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D;D;D;D;D;.;.;D;D;.;.;D;D;.;D;D;D
MetaRNN
Benign
0.0087
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
1.7
L;.;.;L;L;.;.;L;L;.;L;.;L;.;L;L;.;.;L;L;.;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.74
N;.;.;.;.;.;.;.;N;.;N;.;.;.;N;N;.;.;N;N;.;.
REVEL
Benign
0.14
Sift
Uncertain
0.024
D;.;.;.;.;.;.;.;D;.;D;.;.;.;T;D;.;.;D;D;.;.
Sift4G
Benign
0.076
T;.;.;.;.;.;.;.;T;.;T;.;.;.;T;T;.;.;T;T;.;.
Polyphen
0.74, 1.0
.;.;.;.;.;.;.;P;D;.;.;.;.;.;P;D;.;.;.;.;.;.
Vest4
0.35
MVP
0.34
MPC
1.1
ClinPred
0.052
T
GERP RS
5.0
Varity_R
0.54

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs187334123; hg19: chr22-32193632; COSMIC: COSV99836412; COSMIC: COSV99836412; API