NM_001242896.3:c.2354+129_2354+131delGAG

Variant names:

• chr22-31837280-AGAG-A
• rs140455007
• NM_001242896.3:c.2354+129_2354+131delGAG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001242896.3(DEPDC5):​c.2354+129_2354+131delGAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 927,602 control chromosomes in the GnomAD database, including 228 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (59 hom., cov: 31)
  • Exomes 𝑓: 0.018 (169 hom.)
• Consequence: DEPDC5 NM_001242896.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.365
• 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]

ENSG00000285404 (HGNC:):

RNU6-201P (HGNC:47164): (RNA, U6 small nuclear 201, pseudogene)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 22-31837280-AGAG-A is Benign according to our data. Variant chr22-31837280-AGAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 1204196.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0249 (3797/152292) while in subpopulation AFR AF = 0.0412 (1714/41554). AF 95% confidence interval is 0.0396. There are 59 homozygotes in GnomAd4. There are 1876 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3797 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.2354+129_2354+131delGAG		intron_variant	Intron 26 of 42	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.2354+129_2354+131delGAG		intron_variant	Intron 26 of 42		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.1786+18059_1786+18061delGAG		intron_variant	Intron 20 of 20			ENSP00000496158.1

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3792 AN: 152174 Hom.: 58 Cov.: 31

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00384

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.0306

GnomAD4 exome AF: 0.0182 AC: 14104 AN: 775310 Hom.: 169 AF XY: 0.0185 AC XY: 7208 AN XY: 389310

African (AFR) AF: 0.0397 AC: 696 AN: 17548

American (AMR) AF: 0.0204 AC: 358 AN: 17582

Ashkenazi Jewish (ASJ) AF: 0.00941 AC: 143 AN: 15194

East Asian (EAS) AF: 0.00262 AC: 81 AN: 30918

South Asian (SAS) AF: 0.0224 AC: 1065 AN: 47440

European-Finnish (FIN) AF: 0.0241 AC: 822 AN: 34112

Middle Eastern (MID) AF: 0.0191 AC: 79 AN: 4140

European-Non Finnish (NFE) AF: 0.0177 AC: 10132 AN: 572018

Other (OTH) AF: 0.0200 AC: 728 AN: 36358

GnomAD4 genome AF: 0.0249 AC: 3797 AN: 152292 Hom.: 59 Cov.: 31 AF XY: 0.0252 AC XY: 1876 AN XY: 74466

African (AFR) AF: 0.0412 AC: 1714 AN: 41554

American (AMR) AF: 0.0199 AC: 304 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00385 AC: 20 AN: 5190

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4822

European-Finnish (FIN) AF: 0.0244 AC: 259 AN: 10602

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0189 AC: 1286 AN: 68030

Other (OTH) AF: 0.0303 AC: 64 AN: 2112

Alfa AF: 0.0217 Hom.: 3

Bravo AF: 0.0262

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 27, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism

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: rs140455007; hg19: chr22-32233266;