rs1555930038

chr22-31893704-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001242896.3(DEPDC5):c.4156A>C(p.Ile1386Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,644 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: 0.0000021 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.88

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, DEPDC5
• BP4: Computational evidence support a benign effect (MetaRNN=0.29704088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.4156A>C	p.Ile1386Leu	missense_variant	39/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.4156A>C	p.Ile1386Leu	missense_variant	39/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461644 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727128

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, familial focal, with variable foci 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.4156A>C (p.I1386L) alteration is located in exon 39 (coding exon 38) of the DEPDC5 gene. This alteration results from a A to C substitution at nucleotide position 4156, causing the isoleucine (I) at amino acid position 1386 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Familial focal epilepsy with variable foci Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1386 of the DEPDC5 protein (p.Ile1386Leu). This variant is not present in population databases (gnomAD no frequency). 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: 534785). 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	23
Dann	Uncertain	0.99
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;.;.;D;D;.;D;.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.28	N;.;.;.;.;.;N;.;.;.;N;.;.;N;.
REVEL	Benign	0.13
Sift	Benign	0.58	T;.;.;.;.;.;T;.;.;.;T;.;.;T;.
Sift4G	Benign	0.74	T;.;.;.;.;.;T;.;.;.;T;.;.;T;.
Polyphen		0.98	.;.;D;.;.;.;.;.;.;.;.;.;D;.;.
Vest4		0.65
MVP		0.27
MPC		2.1
ClinPred		0.76	D
GERP RS		5.1
Varity_R		0.62

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: rs1555930038; hg19: chr22-32289690;