3-128486824-C-A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_032638.5(GATA2):​c.208G>T​(p.Val70Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000218 in 1,608,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V70V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

GATA2
NM_032638.5 missense

Scores

6
5
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 5.82

Publications

1 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: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.068621635).
BS1
Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000022 (32/1456410) while in subpopulation EAS AF = 0.000785 (31/39466). AF 95% confidence interval is 0.000568. There are 0 homozygotes in GnomAdExome4. There are 15 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GATA2NM_032638.5 linkc.208G>T p.Val70Phe missense_variant Exon 2 of 6 ENST00000341105.7 NP_116027.2 P23769-1
GATA2NM_001145661.2 linkc.208G>T p.Val70Phe missense_variant Exon 3 of 7 NP_001139133.1 P23769-1
GATA2NM_001145662.1 linkc.208G>T p.Val70Phe missense_variant Exon 2 of 6 NP_001139134.1 P23769-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GATA2ENST00000341105.7 linkc.208G>T p.Val70Phe missense_variant Exon 2 of 6 1 NM_032638.5 ENSP00000345681.2 P23769-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152280
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000578
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000892
AC:
21
AN:
235372
AF XY:
0.0000705
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00114
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000176
GnomAD4 exome
AF:
0.0000220
AC:
32
AN:
1456410
Hom.:
0
Cov.:
32
AF XY:
0.0000207
AC XY:
15
AN XY:
724002
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33446
American (AMR)
AF:
0.00
AC:
0
AN:
43888
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25804
East Asian (EAS)
AF:
0.000785
AC:
31
AN:
39466
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84920
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52684
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5754
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1110332
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152398
Hom.:
0
Cov.:
33
AF XY:
0.0000268
AC XY:
2
AN XY:
74522
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41604
American (AMR)
AF:
0.00
AC:
0
AN:
15314
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000579
AC:
3
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68046
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000271
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.000108
AC:
13

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

GATA2 deficiency with susceptibility to MDS/AML Uncertain:1
Jun 04, 2024
Molecular Pathology, Peter Maccallum Cancer Centre
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Acute myeloid leukemia;C3279664:Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections;C3463824:Myelodysplastic syndrome Uncertain:1
-
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.1% (20/17588) (https://gnomad.broadinstitute.org/variant/3-128205667-C-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:472452). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Uncertain:1
Feb 11, 2025
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31723772) -

Acute myeloid leukemia Uncertain:1
Jul 31, 2023
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections Benign:1
Dec 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Uncertain
0.025
T
BayesDel_noAF
Pathogenic
0.22
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.48
T;.;T;T
Eigen
Benign
0.12
Eigen_PC
Benign
0.19
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
.;D;D;D
M_CAP
Pathogenic
0.52
D
MetaRNN
Benign
0.069
T;T;T;T
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Uncertain
2.0
M;M;M;.
PhyloP100
5.8
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
-0.57
N;N;N;N
REVEL
Pathogenic
0.65
Sift
Benign
0.61
T;T;T;T
Sift4G
Benign
0.70
T;T;T;T
Polyphen
0.21
B;P;B;.
Vest4
0.85
MutPred
0.37
Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP
0.90
MPC
1.7
ClinPred
0.082
T
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.29
gMVP
0.67
Mutation Taster
=60/40
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs570531959; hg19: chr3-128205667; API