rs781161922

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The ENST00000341105.7(GATA2):​c.1331C>T​(p.Pro444Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,614,128 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P444R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

GATA2
ENST00000341105.7 missense

Scores

3
8
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.30
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.26529393).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GATA2NM_001145661.2 linkuse as main transcriptc.1331C>T p.Pro444Leu missense_variant 7/7 ENST00000487848.6 NP_001139133.1
GATA2NM_032638.5 linkuse as main transcriptc.1331C>T p.Pro444Leu missense_variant 6/6 ENST00000341105.7 NP_116027.2
GATA2NM_001145662.1 linkuse as main transcriptc.1289C>T p.Pro430Leu missense_variant 6/6 NP_001139134.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GATA2ENST00000341105.7 linkuse as main transcriptc.1331C>T p.Pro444Leu missense_variant 6/61 NM_032638.5 ENSP00000345681 P1P23769-1
GATA2ENST00000487848.6 linkuse as main transcriptc.1331C>T p.Pro444Leu missense_variant 7/71 NM_001145661.2 ENSP00000417074 P1P23769-1

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152252
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
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
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251216
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135798
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461876
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152252
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.0000965
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
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 25, 2023This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 444 of the GATA2 protein (p.Pro444Leu). This variant is present in population databases (rs781161922, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GATA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 574296). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GATA2 protein function. 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxFeb 21, 2024Observed in large population cohorts (gnomAD; internal data); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Acute myeloid leukemia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsOct 01, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.045
T
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
24
DANN
Benign
0.91
DEOGEN2
Uncertain
0.68
D;.;D
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.86
.;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Benign
0.27
T;T;T
MetaSVM
Uncertain
0.61
D
MutationAssessor
Benign
1.1
L;.;L
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-2.2
N;N;N
REVEL
Uncertain
0.50
Sift
Benign
0.43
T;T;T
Sift4G
Benign
0.67
T;T;T
Polyphen
0.38
B;P;B
Vest4
0.44
MutPred
0.28
Loss of glycosylation at S449 (P = 0.0218);.;Loss of glycosylation at S449 (P = 0.0218);
MVP
0.73
MPC
0.18
ClinPred
0.19
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.11
gMVP
0.73

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

LitVar

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

Other links and lift over

dbSNP: rs781161922; hg19: chr3-128199974; COSMIC: COSV62007090; API