3-128486890-A-T

Variant names:

• chr3-128486890-A-T
• rs878855170
• NM_001145661.2:c.142T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_032638.5(GATA2):​c.142T>A​(p.Phe48Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,460,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F48L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GATA2 NM_032638.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 5.93
• Publications: 0 publications found

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: G2P, Labcorp Genetics (formerly Invitae), 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032638.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA2	NM_001145661.2	MANE Plus Clinical	c.142T>A	p.Phe48Ile	missense	Exon 3 of 7	NP_001139133.1	P23769-1
	GATA2	NM_032638.5	MANE Select	c.142T>A	p.Phe48Ile	missense	Exon 2 of 6	NP_116027.2
	GATA2	NM_001145662.1		c.142T>A	p.Phe48Ile	missense	Exon 2 of 6	NP_001139134.1	P23769-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA2	ENST00000341105.7	TSL:1 MANE Select	c.142T>A	p.Phe48Ile	missense	Exon 2 of 6	ENSP00000345681.2	P23769-1
	GATA2	ENST00000487848.6	TSL:1 MANE Plus Clinical	c.142T>A	p.Phe48Ile	missense	Exon 3 of 7	ENSP00000417074.1	P23769-1
	GATA2	ENST00000430265.6	TSL:1	c.142T>A	p.Phe48Ile	missense	Exon 2 of 6	ENSP00000400259.2	P23769-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000245 AC: 6 AN: 244980 AF XY: 0.0000376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000454

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460478 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726410

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000224 AC: 1 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 85822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111588

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.046	D
Polyphen		0.23	B
Vest4		0.80
MVP		0.85
MPC		1.7
ClinPred		0.85	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.74
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs878855170; hg19: chr3-128205733;