3-128485837-G-C

Position:

• chr3-128485837-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_032638.5(GATA2):​c.761C>G​(p.Pro254Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,720 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. P254L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GATA2 NM_032638.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-128485837-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA2	NM_032638.5	c.761C>G	p.Pro254Arg	missense_variant	3/6	ENST00000341105.7	NP_116027.2
GATA2	NM_001145661.2	c.761C>G	p.Pro254Arg	missense_variant	4/7		NP_001139133.1
GATA2	NM_001145662.1	c.761C>G	p.Pro254Arg	missense_variant	3/6		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.761C>G	p.Pro254Arg	missense_variant	3/6	1	NM_032638.5	ENSP00000345681.2
GATA2	ENST00000487848.6	c.761C>G	p.Pro254Arg	missense_variant	4/7	1		ENSP00000417074.1
GATA2	ENST00000430265.6	c.761C>G	p.Pro254Arg	missense_variant	3/6	1		ENSP00000400259.2
GATA2	ENST00000696466.1	c.1043C>G	p.Pro348Arg	missense_variant	5/8			ENSP00000512647.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461720 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

May 27, 2023

This variant is not present in population databases (gnomAD no frequency). 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: 573310). This variant has not been reported in the literature in individuals affected with GATA2-related conditions. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 254 of the GATA2 protein (p.Pro254Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;D
Eigen	Benign	0.17
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	.;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Benign	1.6	L;L;L
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.020	D;D;D
Sift4G	Benign	0.23	T;T;T
Polyphen		0.026	B;D;B
Vest4		0.64
MutPred		0.32		Gain of glycosylation at Y252 (P = 0.0115);Gain of glycosylation at Y252 (P = 0.0115);Gain of glycosylation at Y252 (P = 0.0115);
MVP		0.77
MPC		1.5
ClinPred		0.95	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.73

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: rs387906630; hg19: chr3-128204680;