rs763047721
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_012414.4(RAB3GAP2):c.3028G>A(p.Asp1010Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000073 ( 0 hom. )
Consequence
RAB3GAP2
NM_012414.4 missense
NM_012414.4 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
RAB3GAP2 (HGNC:17168): (RAB3 GTPase activating non-catalytic protein subunit 2) The protein encoded by this gene belongs to the RAB3 protein family, members of which are involved in regulated exocytosis of neurotransmitters and hormones. This protein forms the Rab3 GTPase-activating complex with RAB3GAP1, where it constitutes the regulatory subunit, whereas the latter functions as the catalytic subunit. This gene has the highest level of expression in the brain, consistent with it having a key role in neurodevelopment. Mutations in this gene are associated with Martsolf syndrome.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAB3GAP2 | NM_012414.4 | c.3028G>A | p.Asp1010Asn | missense_variant | 26/35 | ENST00000358951.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAB3GAP2 | ENST00000358951.7 | c.3028G>A | p.Asp1010Asn | missense_variant | 26/35 | 1 | NM_012414.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152172Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000147 AC: 37AN: 251126Hom.: 0 AF XY: 0.000214 AC XY: 29AN XY: 135702
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GnomAD4 exome AF: 0.0000732 AC: 107AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.000114 AC XY: 83AN XY: 727234
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74338
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 23, 2017 | - - |
Martsolf syndrome;C3280214:Warburg micro syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2021 | This sequence change replaces aspartic acid with asparagine at codon 1010 of the RAB3GAP2 protein (p.Asp1010Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs763047721, ExAC 0.1%). This variant has not been reported in the literature in individuals affected with RAB3GAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 436475). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of helix (P = 0.132);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at