NM_001242896.3:c.4156A>C

Variant names:

• chr22-31893704-A-C
• rs1555930038
• NM_001242896.3:c.4156A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 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
• Publications: 0 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29704088).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242896.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	NM_001242896.3	MANE Select	c.4156A>C	p.Ile1386Leu	missense	Exon 39 of 43	NP_001229825.1	O75140-10
	DEPDC5	NM_001364318.2		c.4156A>C	p.Ile1386Leu	missense	Exon 39 of 43	NP_001351247.1	O75140-10
	DEPDC5	NM_001136029.4		c.4129A>C	p.Ile1377Leu	missense	Exon 39 of 43	NP_001129501.1	O75140-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	ENST00000651528.2	MANE Select	c.4156A>C	p.Ile1386Leu	missense	Exon 39 of 43	ENSP00000498382.1	O75140-10
	DEPDC5	ENST00000382112.8	TSL:1	c.4156A>C	p.Ile1386Leu	missense	Exon 39 of 43	ENSP00000371546.4	O75140-10
	DEPDC5	ENST00000433147.2	TSL:1	c.4072A>C	p.Ile1358Leu	missense	Exon 38 of 42	ENSP00000410544.2	H0Y770

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

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111902

Other (OTH) AF: 0.0000331 AC: 2 AN: 60380

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, familial focal, with variable foci 1 (1)
-	1	-	Familial focal epilepsy with variable foci (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.13
Sift	Benign	0.58	T
Sift4G	Benign	0.74	T
Polyphen		0.98	D
Vest4		0.65
MVP		0.27
MPC		2.1
ClinPred		0.76	D
GERP RS		5.1
Varity_R		0.62
Mutation Taster		=22/78	disease causing

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: rs1555930038; hg19: chr22-32289690;