22-31755156-A-G

Position:

• chr22-31755156-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001242896.3(DEPDC5):​c.58+177A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 597,324 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (7 hom.)
• Consequence: DEPDC5 NM_001242896.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.32

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 22-31755156-A-G is Benign according to our data. Variant chr22-31755156-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1208553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31755156-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0079 (1203/152312) while in subpopulation AFR AF= 0.0255 (1061/41572). AF 95% confidence interval is 0.0242. There are 12 homozygotes in gnomad4. There are 573 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.58+177A>G		intron_variant		ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.58+177A>G		intron_variant			NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.58+177A>G		intron_variant				ENSP00000496158.1

Frequencies

GnomAD3 genomes AF: 0.00786 AC: 1196 AN: 152194 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00765

GnomAD4 exome AF: 0.00174 AC: 776 AN: 445012 Hom.: 7 Cov.: 6 AF XY: 0.00187 AC XY: 437 AN XY: 233226

Gnomad4 AFR exome AF: 0.0252

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00698

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000346

Gnomad4 OTH exome AF: 0.00299

GnomAD4 genome AF: 0.00790 AC: 1203 AN: 152312 Hom.: 12 Cov.: 33 AF XY: 0.00769 AC XY: 573 AN XY: 74480

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00508 Hom.: 0

Bravo AF: 0.00907

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.2
DANN	Benign	0.80

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: rs146744706; hg19: chr22-32151142;