3-128485783-C-T

Position:

• chr3-128485783-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000341105.7(GATA2):​c.815G>A​(p.Gly272Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000233 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G272A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: GATA2 ENST00000341105.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.07

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA2	NM_001145661.2	c.815G>A	p.Gly272Glu	missense_variant	4/7	ENST00000487848.6	NP_001139133.1
GATA2	NM_032638.5	c.815G>A	p.Gly272Glu	missense_variant	3/6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145662.1	c.815G>A	p.Gly272Glu	missense_variant	3/6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.815G>A	p.Gly272Glu	missense_variant	3/6	1	NM_032638.5	ENSP00000345681	P1
GATA2	ENST00000487848.6	c.815G>A	p.Gly272Glu	missense_variant	4/7	1	NM_001145661.2	ENSP00000417074	P1
GATA2	ENST00000430265.6	c.815G>A	p.Gly272Glu	missense_variant	3/6	1		ENSP00000400259
GATA2	ENST00000696466.1	c.1097G>A	p.Gly366Glu	missense_variant	5/8			ENSP00000512647

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249432 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461724 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 12, 2023

This variant is present in population databases (rs770511115, gnomAD 0.003%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GATA2 protein function. ClinVar contains an entry for this variant (Variation ID: 472466). This variant has not been reported in the literature in individuals affected with GATA2-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 272 of the GATA2 protein (p.Gly272Glu). -

Acute myeloid leukemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.046	D;T;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.40	B;P;B
Vest4		0.86
MutPred		0.21		Gain of glycosylation at S277 (P = 0.0517);Gain of glycosylation at S277 (P = 0.0517);Gain of glycosylation at S277 (P = 0.0517);
MVP		0.93
MPC		1.7
ClinPred		0.92	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.36
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs770511115; hg19: chr3-128204626; COSMIC: COSV62007964; COSMIC: COSV62007964;