rs1057519307

Variant names:

• chr11-9204090-GTC-G
• rs1057519307
• NM_015213.4:c.517_518delGA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015213.4(DENND5A):​c.517_518delGA​(p.Asp173ProfsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND5A NM_015213.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.14
• Publications: 2 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-9204090-GTC-G is Pathogenic according to our data. Variant chr11-9204090-GTC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 374925.Status of the report is criteria_provided_single_submitter, 1 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.517_518delGA	p.Asp173ProfsTer8	frameshift	Exon 4 of 23	NP_056028.2
	DENND5A	NM_001348749.2		c.445_446delGA	p.Asp149ProfsTer8	frameshift	Exon 3 of 22	NP_001335678.1	A0A7P0Z4N9
	DENND5A	NM_001243254.2		c.517_518delGA	p.Asp173ProfsTer8	frameshift	Exon 4 of 23	NP_001230183.1	Q6IQ26-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DENND5A	ENST00000328194.8	TSL:1 MANE Select	c.517_518delGA	p.Asp173ProfsTer8	frameshift	Exon 4 of 23	ENSP00000328524.3	Q6IQ26-1
	DENND5A	ENST00000679568.1		c.517_518delGA	p.Asp173ProfsTer8	frameshift	Exon 4 of 24	ENSP00000505860.1	A0A7P0T9Z2
	DENND5A	ENST00000965473.1		c.517_518delGA	p.Asp173ProfsTer8	frameshift	Exon 4 of 23	ENSP00000635532.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Developmental and epileptic encephalopathy, 49 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1
Mutation Taster		=3/197	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: rs1057519307;

hg19: chr11-9225637;