3-128481302-G-A

Variant names:

• chr3-128481302-G-A
• rs1060500092
• NM_001145661.2:c.1160C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_032638.5(GATA2):​c.1160C>T​(p.Thr387Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. T387N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GATA2 NM_032638.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.94
• 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_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_032638.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-128481302-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 404089.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

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.1160C>T	p.Thr387Ile	missense	Exon 7 of 7	NP_001139133.1	P23769-1
	GATA2	NM_032638.5	MANE Select	c.1160C>T	p.Thr387Ile	missense	Exon 6 of 6	NP_116027.2
	GATA2	NM_001145662.1		c.1118C>T	p.Thr373Ile	missense	Exon 6 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.1160C>T	p.Thr387Ile	missense	Exon 6 of 6	ENSP00000345681.2	P23769-1
	GATA2	ENST00000487848.6	TSL:1 MANE Plus Clinical	c.1160C>T	p.Thr387Ile	missense	Exon 7 of 7	ENSP00000417074.1	P23769-1
	GATA2	ENST00000430265.6	TSL:1	c.1118C>T	p.Thr373Ile	missense	Exon 6 of 6	ENSP00000400259.2	P23769-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461280 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726966

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.33		Gain of methylation at K389 (P = 0.0361)
MVP		0.89
MPC		3.1
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.86
gMVP		0.82
Mutation Taster		=7/93	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: rs1060500092; hg19: chr3-128200145;