GeneBe

3-128485741-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_032638.5(GATA2):​c.857C>A​(p.Ala286Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A286V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GATA2
NM_032638.5 missense

Scores

3
6
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.64

Publications

0 publications found
Variant links:
Genes affected
GATA2 (HGNC:4171): (GATA binding protein 2) This gene encodes a member of the GATA family of zinc-finger transcription factors that are named for the consensus nucleotide sequence they bind in the promoter regions of target genes. The encoded protein plays an essential role in regulating transcription of genes involved in the development and proliferation of hematopoietic and endocrine cell lineages. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Mar 2009]
GATA2 Gene-Disease associations (from GenCC):
  • deafness-lymphedema-leukemia syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
  • GATA2 deficiency with susceptibility to MDS/AML
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • monocytopenia with susceptibility to infections
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
  • acute myeloid leukemia
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • myelodysplastic syndrome
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-128485741-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211062.
BP4
Computational evidence support a benign effect (MetaRNN=0.29344594).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GATA2NM_032638.5 linkc.857C>A p.Ala286Asp missense_variant Exon 3 of 6 ENST00000341105.7 NP_116027.2 P23769-1
GATA2NM_001145661.2 linkc.857C>A p.Ala286Asp missense_variant Exon 4 of 7 NP_001139133.1 P23769-1
GATA2NM_001145662.1 linkc.857C>A p.Ala286Asp missense_variant Exon 3 of 6 NP_001139134.1 P23769-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GATA2ENST00000341105.7 linkc.857C>A p.Ala286Asp missense_variant Exon 3 of 6 1 NM_032638.5 ENSP00000345681.2 P23769-1
GATA2ENST00000487848.6 linkc.857C>A p.Ala286Asp missense_variant Exon 4 of 7 1 ENSP00000417074.1 P23769-1
GATA2ENST00000430265.6 linkc.857C>A p.Ala286Asp missense_variant Exon 3 of 6 1 ENSP00000400259.2 P23769-2
GATA2ENST00000696466.1 linkc.1139C>A p.Ala380Asp missense_variant Exon 5 of 8 ENSP00000512647.1 A0A8Q3WLD0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461578
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727066
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44698
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86198
European-Finnish (FIN)
AF:
0.0000188
AC:
1
AN:
53268
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111954
Other (OTH)
AF:
0.00
AC:
0
AN:
60392
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Uncertain
0.086
D
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.53
D;.;D
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.051
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.73
.;T;T
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.29
T;T;T
MetaSVM
Uncertain
0.47
D
MutationAssessor
Benign
1.2
L;L;L
PhyloP100
5.6
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-1.5
N;N;N
REVEL
Uncertain
0.35
Sift
Benign
0.11
T;T;T
Sift4G
Benign
0.11
T;T;T
Polyphen
0.29
B;B;B
Vest4
0.45
MutPred
0.39
Gain of glycosylation at S290 (P = 0.0135);Gain of glycosylation at S290 (P = 0.0135);Gain of glycosylation at S290 (P = 0.0135);
MVP
0.68
MPC
0.95
ClinPred
0.45
T
GERP RS
2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.26
gMVP
0.62
Mutation Taster
=26/74
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs797045592; hg19: chr3-128204584; API