rs1057519309

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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 (★).

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DENND5A	NM_015213.4	c.1622A>G	p.Asp541Gly	missense_variant	Exon 7 of 23	ENST00000328194.8	NP_056028.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DENND5A	ENST00000328194.8	c.1622A>G	p.Asp541Gly	missense_variant	Exon 7 of 23	1	NM_015213.4	ENSP00000328524.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 49 Pathogenic:1 Uncertain:1

Nov 19, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 16, 2018

SIB Swiss Institute of Bioinformatics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Uncertain Significance, for Epileptic encephalopathy, early infantile, 49, Autosomal Recessive inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PM1-Supporting => PM1 downgraded in strength to Supporting. -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.047	D;T
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.50		Loss of stability (P = 0.0765);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519309; hg19: chr11-9200454;