11-9169877-AC-GT

Variant names:

• chr11-9169877-AC-GT
• NM_015213.4:c.2129_2130delGTinsAC
• DENND5A p.Arg710His

Variant summary

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

The NM_015213.4(DENND5A):​c.2129_2130delGTinsAC​(p.Arg710His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R710C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND5A NM_015213.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.72
• Publications: 0 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: G2P, Genomics England PanelApp, Baylor College of Medicine Research Center, Labcorp Genetics (formerly Invitae)
• Tourette syndrome

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.2129_2130delGTinsAC	p.Arg710His	missense	N/A	NP_056028.2
	DENND5A	NM_001348749.2		c.2057_2058delGTinsAC	p.Arg686His	missense	N/A	NP_001335678.1	A0A7P0Z4N9
	DENND5A	NM_001243254.2		c.2129_2130delGTinsAC	p.Arg710His	missense	N/A	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.2129_2130delGTinsAC	p.Arg710His	missense	N/A	ENSP00000328524.3	Q6IQ26-1
	DENND5A	ENST00000679568.1		c.2129_2130delGTinsAC	p.Arg710His	missense	N/A	ENSP00000505860.1	A0A7P0T9Z2
	DENND5A	ENST00000965473.1		c.2129_2130delGTinsAC	p.Arg710His	missense	N/A	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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7

Splicing

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

hg19: chr11-9191424;