rs760230147

chr3-128486376-CAAAG-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_032638.5(GATA2):c.230-12_230-9del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,596,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: GATA2 NM_032638.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.198

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 -9 ACMG points.

• BP6: Variant 3-128486376-CAAAG-C is Benign according to our data. Variant chr3-128486376-CAAAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 412753.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000237 (36/152070) while in subpopulation NFE AF= 0.000485 (33/68004). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA2	NM_001145661.2	c.230-12_230-9del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000487848.6
GATA2	NM_032638.5	c.230-12_230-9del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000341105.7
GATA2	NM_001145662.1	c.230-12_230-9del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA2	ENST00000341105.7	c.230-12_230-9del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_032638.5	P1
GATA2	ENST00000487848.6	c.230-12_230-9del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001145661.2	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151952 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000485

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000216 AC: 47 AN: 217586 Hom.: 0 AF XY: 0.000184 AC XY: 22 AN XY: 119510

Gnomad AFR exome AF: 0.0000786

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000680

Gnomad NFE exome AF: 0.000445

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.000345 AC: 498 AN: 1444650 Hom.: 0 AF XY: 0.000309 AC XY: 222 AN XY: 718046

Gnomad4 AFR exome AF: 0.0000299

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: 0.000378

Gnomad4 NFE exome AF: 0.000425

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74322

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.000208

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

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

Jan 25, 2021

DNA sequence analysis of the GATA2 gene demonstrated a sequence change in intron 2, c.230-12_230-9del. This 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 low population frequency of 0.02% (dbSNP rs780435066). This sequence change is not clearly predicted to have a deleterious effect on splicing based on in silico splice prediction programs. It is possible that this sequence change represents a benign sequence change in the GATA2 gene that has not been identified to date. The functional significance of this sequence change is not known at present and its contribution to this patient's disease phenotype cannot definitively be determined. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Sep 03, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs760230147; hg19: chr3-128205219;