chr22-31754937-G-A

Variant names:

• chr22-31754937-G-A
• rs2075191238
• NM_001242896.3:c.16G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001242896.3(DEPDC5):​c.16G>A​(p.Val6Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,198 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: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

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]

ENSG00000285404 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17955095).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.16G>A	p.Val6Ile	missense_variant	Exon 2 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.16G>A	p.Val6Ile	missense_variant	Exon 2 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.16G>A	p.Val6Ile	missense_variant	Exon 1 of 21			ENSP00000496158.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 24, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.0045
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D;D;D;.;.;D;D;.;.;.;D;D;.;D;D;D
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.18	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	0.20	N;.;.;N;N;.;.;.;N;N;.;N;.;N;.;N;.;N;.;.;N;N;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.15	N;.;.;.;.;.;N;.;.;N;.;N;.;.;.;N;.;N;.;.;N;N;.;.
REVEL	Benign	0.037
Sift	Benign	0.056	T;.;.;.;.;.;T;.;.;T;.;T;.;.;.;T;.;T;.;.;T;T;.;.
Sift4G	Benign	0.29	T;.;.;.;.;.;T;.;.;T;.;T;.;.;.;T;.;T;.;.;T;T;.;.
Polyphen		0.0040, 0.41	.;.;.;.;.;.;.;.;B;B;.;.;.;.;.;B;.;B;.;.;.;.;.;.
Vest4		0.37
MutPred		0.30		Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);Gain of catalytic residue at V6 (P = 0.0243);
MVP		0.13
MPC		0.44
ClinPred		0.71	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064

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: rs2075191238; hg19: chr22-32150923;