rs570531959

Positions:

chr3-128486824-C-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

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

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.82

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.068621635).

BP6

Variant 3-128486824-C-A is Benign according to our data. Variant chr3-128486824-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472452.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome 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 gnomad4_exome. There are 15 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GATA2	NM_001145661.2 linkuse as main transcript	c.208G>T	p.Val70Phe	missense_variant	3/7	ENST00000487848.6
GATA2	NM_032638.5 linkuse as main transcript	c.208G>T	p.Val70Phe	missense_variant	2/6	ENST00000341105.7
GATA2	NM_001145662.1 linkuse as main transcript	c.208G>T	p.Val70Phe	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA2	ENST00000341105.7 linkuse as main transcript	c.208G>T	p.Val70Phe	missense_variant	2/6	1	NM_032638.5	P1	P23769-1
GATA2	ENST00000487848.6 linkuse as main transcript	c.208G>T	p.Val70Phe	missense_variant	3/7	1	NM_001145661.2	P1	P23769-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152280

Hom.:

Cov.:

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

GnomAD3 exomes

AF:

0.0000892

AC:

AN:

235372

Hom.:

AF XY:

0.0000705

AC XY:

AN XY:

127720

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.0000220

AC:

AN:

1456410

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

724002

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000785

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152398

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acute myeloid leukemia;C3279664:Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections;C3463824:Myelodysplastic syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Oct 28, 2022

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. -

Acute myeloid leukemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 31, 2023

- -

Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

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

M_CAP

Pathogenic

0.52

MetaRNN

Benign

0.069

T;T;T;T

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.0

M;M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.90

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

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.29

gMVP

0.67

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over