16-23470135-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015044.4(GGA2):​c.1481G>A​(p.Arg494Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000405 in 1,605,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

GGA2
NM_015044.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.42
Variant links:
Genes affected
GGA2 (HGNC:16064): (golgi associated, gamma adaptin ear containing, ARF binding protein 2) This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) family. This family includes ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. This family member may play a significant role in cargo molecules regulation and clathrin-coated vesicle assembly. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22832942).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GGA2NM_015044.4 linkc.1481G>A p.Arg494Gln missense_variant Exon 15 of 17 ENST00000309859.8 NP_055859.1 Q9UJY4
GGA2XM_047433801.1 linkc.1451G>A p.Arg484Gln missense_variant Exon 16 of 18 XP_047289757.1
GGA2XM_047433802.1 linkc.1370G>A p.Arg457Gln missense_variant Exon 15 of 17 XP_047289758.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GGA2ENST00000309859.8 linkc.1481G>A p.Arg494Gln missense_variant Exon 15 of 17 1 NM_015044.4 ENSP00000311962.4 Q9UJY4
GGA2ENST00000567468.5 linkc.625-4737G>A intron_variant Intron 7 of 7 2 ENSP00000454455.1 H3BMM6

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152076
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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
GnomAD3 exomes
AF:
0.0000449
AC:
11
AN:
244964
Hom.:
0
AF XY:
0.0000302
AC XY:
4
AN XY:
132410
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000982
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000433
AC:
63
AN:
1453822
Hom.:
0
Cov.:
30
AF XY:
0.0000443
AC XY:
32
AN XY:
722868
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000385
Gnomad4 EAS exome
AF:
0.0000762
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000469
Gnomad4 OTH exome
AF:
0.0000665
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152076
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74268
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
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
Alfa
AF:
0.0000764
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 27, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1481G>A (p.R494Q) alteration is located in exon 15 (coding exon 15) of the GGA2 gene. This alteration results from a G to A substitution at nucleotide position 1481, causing the arginine (R) at amino acid position 494 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.44
CADD
Pathogenic
26
DANN
Benign
0.96
DEOGEN2
Benign
0.075
T
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.19
FATHMM_MKL
Benign
0.57
D
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.23
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.2
L
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.050
N
REVEL
Benign
0.17
Sift
Benign
0.52
T
Sift4G
Benign
0.47
T
Polyphen
0.97
D
Vest4
0.14
MutPred
0.40
Gain of phosphorylation at Y492 (P = 0.1296);
MVP
0.39
MPC
0.41
ClinPred
0.19
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.031
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs202188100; hg19: chr16-23481456; API