3-128486117-G-C

Variant names:

• chr3-128486117-G-C
• rs34799090
• NM_001145661.2:c.481C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032638.5(GATA2):​c.481C>G​(p.Pro161Ala) variant causes a missense change. The variant allele was found at a frequency of 0.012 in 1,611,704 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign 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. P161L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0083 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (159 hom.)
• Consequence: GATA2 NM_032638.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13 O:1
• Conservation: PhyloP100: 5.21
• Publications: 28 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0082579255).
• BP6: Variant 3-128486117-G-C is Benign according to our data. Variant chr3-128486117-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134465.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00828 (1261/152268) while in subpopulation NFE AF = 0.0139 (946/67996). AF 95% confidence interval is 0.0132. There are 9 homozygotes in GnomAd4. There are 544 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1261 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.481C>G	p.Pro161Ala	missense	Exon 4 of 7	NP_001139133.1	P23769-1
	GATA2	NM_032638.5	MANE Select	c.481C>G	p.Pro161Ala	missense	Exon 3 of 6	NP_116027.2
	GATA2	NM_001145662.1		c.481C>G	p.Pro161Ala	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.481C>G	p.Pro161Ala	missense	Exon 3 of 6	ENSP00000345681.2	P23769-1
	GATA2	ENST00000487848.6	TSL:1 MANE Plus Clinical	c.481C>G	p.Pro161Ala	missense	Exon 4 of 7	ENSP00000417074.1	P23769-1
	GATA2	ENST00000430265.6	TSL:1	c.481C>G	p.Pro161Ala	missense	Exon 3 of 6	ENSP00000400259.2	P23769-2

Frequencies

GnomAD3 genomes AF: 0.00830 AC: 1263 AN: 152150 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00820 AC: 1984 AN: 241956 AF XY: 0.00825

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00210

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.00870

GnomAD4 exome AF: 0.0124 AC: 18130 AN: 1459436 Hom.: 159 Cov.: 36 AF XY: 0.0122 AC XY: 8880 AN XY: 725780

African (AFR) AF: 0.00182 AC: 61 AN: 33464

American (AMR) AF: 0.00382 AC: 170 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 417 AN: 26030

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39626

South Asian (SAS) AF: 0.00289 AC: 248 AN: 85774

European-Finnish (FIN) AF: 0.00318 AC: 168 AN: 52912

Middle Eastern (MID) AF: 0.00647 AC: 36 AN: 5566

European-Non Finnish (NFE) AF: 0.0149 AC: 16507 AN: 1111354

Other (OTH) AF: 0.00865 AC: 521 AN: 60238

GnomAD4 genome AF: 0.00828 AC: 1261 AN: 152268 Hom.: 9 Cov.: 32 AF XY: 0.00731 AC XY: 544 AN XY: 74446

African (AFR) AF: 0.00301 AC: 125 AN: 41546

American (AMR) AF: 0.00581 AC: 89 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0139 AC: 946 AN: 67996

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.0112 Hom.: 3

Bravo AF: 0.00838

TwinsUK AF: 0.0170 AC: 63

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0126 AC: 108

ExAC AF: 0.00814 AC: 987

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (7)
-	1	3	not provided (4)
-	-	1	Deafness-lymphedema-leukemia syndrome (1)
-	-	1	Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections (1)
-	-	1	GATA2-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.045
Eigen_PC	Benign	0.090
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0083	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.8	L
PhyloP100		5.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.35
Sift	Benign	0.28	T
Sift4G	Benign	0.47	T
Polyphen		0.030	B
Vest4		0.54
MVP		0.75
MPC		1.4
ClinPred		0.028	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
gMVP		0.41
Mutation Taster		=86/14	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: rs34799090; hg19: chr3-128204960; COSMIC: COSV62007567;