chr11-9139741-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_015213.4(DENND5A):​c.3794G>A​(p.Arg1265His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

DENND5A
NM_015213.4 missense

Scores

2
6
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.91
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DENND5A. . Gene score misZ 2.3781 (greater than the threshold 3.09). Trascript score misZ 3.1917 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 49, Tourette syndrome.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DENND5ANM_015213.4 linkuse as main transcriptc.3794G>A p.Arg1265His missense_variant 23/23 ENST00000328194.8 NP_056028.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DENND5AENST00000328194.8 linkuse as main transcriptc.3794G>A p.Arg1265His missense_variant 23/231 NM_015213.4 ENSP00000328524 P3Q6IQ26-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152090
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461802
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152090
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 17, 2024The c.3794G>A (p.R1265H) alteration is located in exon 23 (coding exon 23) of the DENND5A gene. This alteration results from a G to A substitution at nucleotide position 3794, causing the arginine (R) at amino acid position 1265 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 31, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with DENND5A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1265 of the DENND5A protein (p.Arg1265His). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.037
T
BayesDel_noAF
Benign
-0.29
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.027
T
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D
M_CAP
Benign
0.024
T
MetaRNN
Uncertain
0.60
D
MetaSVM
Benign
-0.55
T
MutationAssessor
Uncertain
2.0
M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.20
Sift
Benign
0.17
T
Sift4G
Benign
0.23
T
Polyphen
1.0
D
Vest4
0.70
MutPred
0.52
Gain of catalytic residue at L1267 (P = 0.0835);
MVP
0.25
MPC
0.53
ClinPred
0.79
D
GERP RS
5.7
Varity_R
0.11
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1015518442; hg19: chr11-9161288; COSMIC: COSV60231043; COSMIC: COSV60231043; API