rs753645971

chr3-128486153-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G149A) 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:3 B:2
• Conservation: PhyloP100: 3.27

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22076195).
• BP6: Variant 3-128486153-C-T is Benign according to our data. Variant chr3-128486153-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 404080.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}. Variant chr3-128486153-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome 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 gnomad4_exome. There are 36 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA2	NM_001145661.2	c.445G>A	p.Gly149Arg	missense_variant	4/7	ENST00000487848.6
GATA2	NM_032638.5	c.445G>A	p.Gly149Arg	missense_variant	3/6	ENST00000341105.7
GATA2	NM_001145662.1	c.445G>A	p.Gly149Arg	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA2	ENST00000341105.7	c.445G>A	p.Gly149Arg	missense_variant	3/6	1	NM_032638.5	P1
GATA2	ENST00000487848.6	c.445G>A	p.Gly149Arg	missense_variant	4/7	1	NM_001145661.2	P1

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

GnomAD3 exomes AF: 0.000122 AC: 23 AN: 188602 Hom.: 0 AF XY: 0.0000884 AC XY: 9 AN XY: 101812

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 SAS exome AF: 0.0000390

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000614

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000447

Gnomad4 OTH exome AF: 0.0000847

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

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000505 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 28, 2020

DNA sequence analysis of the GATA2 gene demonstrated a sequence change, c.445G>A, in exon 3 that results in an amino acid change, p.Gly149Arg. This sequence change does not appear to have been previously described in patients with GATA2-related disorders and has been described in the gnomAD database with a frequency of 0.053% in the Latino sub-population (dbSNP rs753645971). The p.Gly149Arg change affects a poorly conserved amino acid residue located in a domain of the GATA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly149Arg substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly149Arg change remains unknown at this time. -

Acute myeloid leukemia;C3279664:Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections;C3463824:Myelodysplastic syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a patient with gastric cancer and in a patient with leukemia (AML); however, it is unclear whether the variant was germline or somatic in the latter individual (Aguirre-Ruiz et al., 2020; Herrera-Pariente et al., 2021); This variant is associated with the following publications: (PMID: 30755392, 33255857, 33525650) -

GATA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;.;T;T
Eigen	Benign	0.053
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.69	N;N;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.46	N;N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.079	T;T;T;D
Sift4G	Benign	0.31	T;T;T;D
Polyphen		0.95	P;D;P;.
Vest4		0.52
MutPred		0.36		Gain of methylation at G149 (P = 0.0053);Gain of methylation at G149 (P = 0.0053);Gain of methylation at G149 (P = 0.0053);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

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