rs141800945

Variant names:

• chr3-128485769-T-C
• rs141800945
• NM_001145661.2:c.829A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-128485769-T-C
• chr3-128485769-T-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_032638.5(GATA2):​c.829A>G​(p.Ser277Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,613,988 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. S277N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: GATA2 NM_032638.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 5.06
• Publications: 6 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13712156).
• BS2: High AC in GnomAd4 at 15 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.829A>G	p.Ser277Gly	missense	Exon 4 of 7	NP_001139133.1	P23769-1
	GATA2	NM_032638.5	MANE Select	c.829A>G	p.Ser277Gly	missense	Exon 3 of 6	NP_116027.2
	GATA2	NM_001145662.1		c.829A>G	p.Ser277Gly	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.829A>G	p.Ser277Gly	missense	Exon 3 of 6	ENSP00000345681.2	P23769-1
	GATA2	ENST00000487848.6	TSL:1 MANE Plus Clinical	c.829A>G	p.Ser277Gly	missense	Exon 4 of 7	ENSP00000417074.1	P23769-1
	GATA2	ENST00000430265.6	TSL:1	c.829A>G	p.Ser277Gly	missense	Exon 3 of 6	ENSP00000400259.2	P23769-2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 249184 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000281

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1461734 Hom.: 0 Cov.: 32 AF XY: 0.000136 AC XY: 99 AN XY: 727172

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53342

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

European-Non Finnish (NFE) AF: 0.000163 AC: 181 AN: 1111994

Other (OTH) AF: 0.000116 AC: 7 AN: 60388

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74432

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	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	-	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.052
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.76	N
PhyloP100		5.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.34
Sift	Benign	0.33	T
Sift4G	Benign	0.24	T
Polyphen		0.0010	B
Vest4		0.25
MVP		0.66
MPC		1.3
ClinPred		0.088	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.21
gMVP		0.47
Mutation Taster		=36/64	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: rs141800945; hg19: chr3-128204612; COSMIC: COSV108866099;