chr22-31857524-A-G

Position:

• chr22-31857524-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001242896.3(DEPDC5):​c.3235A>G​(p.Thr1079Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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=0.18715656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.3235A>G	p.Thr1079Ala	missense_variant	32/43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.3235A>G	p.Thr1079Ala	missense_variant	32/43		NM_001242896.3	ENSP00000498382	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial focal epilepsy with variable foci Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2021

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. This variant has not been reported in the literature in individuals with DEPDC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 238678). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 1079 of the DEPDC5 protein (p.Thr1079Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	.;.;.;.;.;T;.;.;.;.;T;.;.;.;.
Eigen	Benign	0.039
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;.;.;D;D;.;D;.;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;.;L;.;.;L;.;.;.;.;L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.60	N;.;.;.;.;.;N;.;.;.;N;.;.;N;.
REVEL	Benign	0.072
Sift	Benign	0.18	T;.;.;.;.;.;T;.;.;.;T;.;.;T;.
Sift4G	Benign	0.14	T;.;.;.;.;.;T;.;.;.;T;.;.;T;.
Polyphen		0.0040	.;.;B;.;.;.;.;.;.;.;.;.;B;.;.
Vest4		0.56
MVP		0.23
MPC		0.39
ClinPred		0.76	D
GERP RS		5.7
Varity_R		0.25

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

Other links and lift over

dbSNP: rs878854278; hg19: chr22-32253510;