NM_015213.4:c.1622A>G

Variant names:

• chr11-9178907-T-C
• rs1057519309
• NM_015213.4:c.1622A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015213.4(DENND5A):​c.1622A>G​(p.Asp541Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D541N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DENND5A NM_015213.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.92
• Publications: 3 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1622A>G	p.Asp541Gly	missense	Exon 7 of 23	NP_056028.2
	DENND5A	NM_001348749.2		c.1550A>G	p.Asp517Gly	missense	Exon 6 of 22	NP_001335678.1	A0A7P0Z4N9
	DENND5A	NM_001243254.2		c.1622A>G	p.Asp541Gly	missense	Exon 7 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.1622A>G	p.Asp541Gly	missense	Exon 7 of 23	ENSP00000328524.3	Q6IQ26-1
	DENND5A	ENST00000679568.1		c.1622A>G	p.Asp541Gly	missense	Exon 7 of 24	ENSP00000505860.1	A0A7P0T9Z2
	DENND5A	ENST00000965473.1		c.1622A>G	p.Asp541Gly	missense	Exon 7 of 23	ENSP00000635532.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Developmental and epileptic encephalopathy, 49 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.50		Loss of stability (P = 0.0765)
MVP		0.58
MPC		1.4
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.52
gMVP		0.74
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: 1
DS_DL_spliceai		0.96		Position offset: -49

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057519309; hg19: chr11-9200454;