3-128486153-C-T

Variant names:

• chr3-128486153-C-T
• rs753645971
• NM_001145661.2:c.445G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_032638.5(GATA2):​c.445G>A​(p.Gly149Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,581,142 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). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G149E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: GATA2 NM_032638.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 3.27
• Publications: 3 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22076195).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000553 (79/1428958) while in subpopulation AMR AF = 0.000614 (24/39060). AF 95% confidence interval is 0.000424. There are 0 homozygotes in GnomAdExome4. There are 36 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 13 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.445G>A	p.Gly149Arg	missense	Exon 4 of 7	NP_001139133.1	P23769-1
	GATA2	NM_032638.5	MANE Select	c.445G>A	p.Gly149Arg	missense	Exon 3 of 6	NP_116027.2
	GATA2	NM_001145662.1		c.445G>A	p.Gly149Arg	missense	Exon 3 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.445G>A	p.Gly149Arg	missense	Exon 3 of 6	ENSP00000345681.2	P23769-1
	GATA2	ENST00000487848.6	TSL:1 MANE Plus Clinical	c.445G>A	p.Gly149Arg	missense	Exon 4 of 7	ENSP00000417074.1	P23769-1
	GATA2	ENST00000430265.6	TSL:1	c.445G>A	p.Gly149Arg	missense	Exon 3 of 6	ENSP00000400259.2	P23769-2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000122 AC: 23 AN: 188602 AF XY: 0.0000884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000545

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000504

Gnomad OTH exome AF: 0.000412

GnomAD4 exome AF: 0.0000553 AC: 79 AN: 1428958 Hom.: 0 Cov.: 36 AF XY: 0.0000509 AC XY: 36 AN XY: 707590

African (AFR) AF: 0.00 AC: 0 AN: 33078

American (AMR) AF: 0.000614 AC: 24 AN: 39060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25488

East Asian (EAS) AF: 0.00 AC: 0 AN: 38404

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5076

European-Non Finnish (NFE) AF: 0.0000447 AC: 49 AN: 1096308

Other (OTH) AF: 0.0000847 AC: 5 AN: 59062

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000505 AC: 6

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Acute myeloid leukemia (1)
-	1	-	Acute myeloid leukemia;C3279664:Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections;C3463824:Myelodysplastic syndrome (1)
-	-	1	Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections (1)
-	1	-	GATA2 deficiency with susceptibility to MDS/AML (1)
-	-	1	GATA2-related disorder (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.053
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.69	N
PhyloP100		3.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.46	N
REVEL	Uncertain	0.40
Sift	Benign	0.079	T
Sift4G	Benign	0.31	T
Polyphen		0.95	P
Vest4		0.52
MutPred		0.36		Gain of methylation at G149 (P = 0.0053)
MVP		0.76
MPC		0.87
ClinPred		0.14	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.090
gMVP		0.39
Mutation Taster		=81/19	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

Other links and lift over

dbSNP: rs753645971; hg19: chr3-128204996; COSMIC: COSV62003528; COSMIC: COSV62003528;