rs777726701

Positions:

• chr3-128481060-C-A
• chr3-128481060-C-G
• chr3-128481060-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032638.5(GATA2):​c.1402G>T​(p.Gly468Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,446,542 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. G468S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GATA2 NM_032638.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA2	NM_001145661.2	c.1402G>T	p.Gly468Cys	missense_variant	7/7	ENST00000487848.6
GATA2	NM_032638.5	c.1402G>T	p.Gly468Cys	missense_variant	6/6	ENST00000341105.7
GATA2	NM_001145662.1	c.1360G>T	p.Gly454Cys	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA2	ENST00000341105.7	c.1402G>T	p.Gly468Cys	missense_variant	6/6	1	NM_032638.5	P1
GATA2	ENST00000487848.6	c.1402G>T	p.Gly468Cys	missense_variant	7/7	1	NM_001145661.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1446542 Hom.: 0 Cov.: 31 AF XY: 0.00000418 AC XY: 3 AN XY: 717084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.1402G>T (p.G468C) alteration is located in exon 6 (coding exon 5) of the GATA2 gene. This alteration results from a G to T substitution at nucleotide position 1402, causing the glycine (G) at amino acid position 468 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.074	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.46
MutPred		0.14		Loss of glycosylation at P470 (P = 0.0411);.;Loss of glycosylation at P470 (P = 0.0411);
MVP		0.83
MPC		0.65
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.40
gMVP		0.66

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: rs777726701; hg19: chr3-128199903;