rs1057519310

Variant names:

• chr11-9139723-TG-T
• rs1057519310
• NM_015213.4:c.3811delC

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_015213.4(DENND5A):​c.3811delC​(p.Gln1271ArgfsTer67) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND5A NM_015213.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.07
• Publications: 1 publications found

Genes affected

DENND5A (HGNC:19344): (DENN domain containing 5A) This gene encodes a DENN-domain-containing protein that functions as a RAB-activating guanine nucleotide exchange factor (GEF). This protein catalyzes the conversion of GDP to GTP and thereby converts inactive GDP-bound Rab proteins into their active GTP-bound form. The encoded protein is recruited by RAB6 onto Golgi membranes and is therefore referred to as RAB6-interacting protein 1. This protein binds with RAB39 as well. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Mutations in this gene are associated with early infantile epileptic encephalopathy-49. [provided by RefSeq, Feb 2017]

DENND5A Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 49

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Baylor College of Medicine Research Center
• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0137 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-9139723-TG-T is Pathogenic according to our data. Variant chr11-9139723-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 374928.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015213.4. 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
	DENND5A	NM_015213.4	MANE Select	c.3811delC	p.Gln1271ArgfsTer67	frameshift	Exon 23 of 23	NP_056028.2
	DENND5A	NM_001348749.2		c.3739delC	p.Gln1247ArgfsTer67	frameshift	Exon 22 of 22	NP_001335678.1	A0A7P0Z4N9
	DENND5A	NM_001348750.2		c.3523delC	p.Gln1175ArgfsTer67	frameshift	Exon 24 of 24	NP_001335679.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND5A	ENST00000328194.8	TSL:1 MANE Select	c.3811delC	p.Gln1271ArgfsTer67	frameshift	Exon 23 of 23	ENSP00000328524.3	Q6IQ26-1
	DENND5A	ENST00000679568.1		c.3871delC	p.Gln1291ArgfsTer67	frameshift	Exon 24 of 24	ENSP00000505860.1	A0A7P0T9Z2
	DENND5A	ENST00000965473.1		c.3808delC	p.Gln1270ArgfsTer67	frameshift	Exon 23 of 23	ENSP00000635532.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy, 49 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057519310;

hg19: chr11-9161270;