rs201776005

chr22-31802725-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM2 PP2 BP4_Moderate BP6 BS1

The NM_001242896.3(DEPDC5):c.968A>G(p.Asn323Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,588,148 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 9.08

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 Likely_benign. Variant got -4 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=0.2200622).
• BP6: Variant 22-31802725-A-G is Benign according to our data. Variant chr22-31802725-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 466500.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000217 (33/152096) while in subpopulation NFE AF= 0.000367 (25/68030). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.968A>G	p.Asn323Ser	missense_variant	15/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.968A>G	p.Asn323Ser	missense_variant	15/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 34 AN: 230676 Hom.: 0 AF XY: 0.000143 AC XY: 18 AN XY: 125500

Gnomad AFR exome AF: 0.000138

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000277

Gnomad OTH exome AF: 0.000375

GnomAD4 exome AF: 0.000294 AC: 422 AN: 1436052 Hom.: 1 Cov.: 30 AF XY: 0.000265 AC XY: 189 AN XY: 713606

Gnomad4 AFR exome AF: 0.0000618

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: 0.000346

Gnomad4 OTH exome AF: 0.000658

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152096 Hom.: 0 Cov.: 31 AF XY: 0.000229 AC XY: 17 AN XY: 74290

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000239 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.000483 AC: 4

ExAC AF: 0.000141 AC: 17

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2019	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Familial focal epilepsy with variable foci Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 323 of the DEPDC5 protein (p.Asn323Ser). This variant is present in population databases (rs201776005, gnomAD 0.03%). 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: 466500). 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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;.;.;D;D;.;.;D;D;.;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	2.0	M;.;.;M;M;.;.;M;M;.;M;.;M;.;M;M;.;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.5	N;.;.;.;.;.;.;.;N;.;N;.;.;.;N;N;.;.;N;N;.;.
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D;.;.;.;.;.;.;.;D;.;D;.;.;.;D;D;.;.;D;D;.;.
Sift4G	Uncertain	0.028	D;.;.;.;.;.;.;.;D;.;D;.;.;.;D;D;.;.;D;D;.;.
Polyphen		0.84, 0.98	.;.;.;.;.;.;.;P;D;.;.;.;.;.;P;D;.;.;.;.;.;.
Vest4		0.85
MVP		0.37
MPC		1.1
ClinPred		0.28	T
GERP RS		5.7
Varity_R		0.57

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: rs201776005; hg19: chr22-32198711;