rs373578854

Variant names:

• chr22-31765014-G-A
• rs373578854
• NM_001242896.3:c.233G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-31765014-G-A
• chr22-31765014-G-C
• chr22-31765014-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001242896.3(DEPDC5):​c.233G>A​(p.Arg78Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R78W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.17
• Publications: 2 publications found

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]

DEPDC5 Gene-Disease associations (from GenCC):

• epilepsy, familial focal, with variable foci 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Illumina, G2P
• focal epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant epilepsy with auditory features

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial focal epilepsy with variable foci

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Brugada syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000285404 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08122468).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.233G>A	p.Arg78Gln	missense_variant	Exon 5 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.233G>A	p.Arg78Gln	missense_variant	Exon 5 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.233G>A	p.Arg78Gln	missense_variant	Exon 4 of 21			ENSP00000496158.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 249530 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461812 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111960

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial focal epilepsy with variable foci Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.016	.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;.;.;D;D;.;.;.;D;D;.;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.081	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N;.;.;N;N;.;.;.;N;N;.;N;.;N;.;N;.;N;.;.;N;N;.;.;.
PhyloP100		7.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.53	N;.;.;.;.;.;.;.;.;N;.;N;.;.;.;N;.;N;.;.;N;N;.;.;.
REVEL	Benign	0.096
Sift	Benign	1.0	T;.;.;.;.;.;.;.;.;T;.;T;.;.;.;T;.;T;.;.;T;T;.;.;.
Sift4G	Benign	0.78	T;.;.;.;.;.;.;.;.;T;.;T;.;.;.;T;.;T;.;.;T;T;.;.;.
Polyphen		0.0060, 0.071	.;.;.;.;.;.;.;.;B;B;.;.;.;.;.;B;.;B;.;.;.;.;.;.;.
Vest4		0.47
MutPred		0.38		Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);Loss of catalytic residue at R78 (P = 0.1288);.;Loss of catalytic residue at R78 (P = 0.1288);
MVP		0.31
MPC		0.53
ClinPred		0.18	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs373578854; hg19: chr22-32161000;