3-128481949-G-A

Variant names:

• chr3-128481949-G-A
• rs769196688
• NM_032638.5:c.1018-5C>T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_032638.5(GATA2):​c.1018-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,018 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: GATA2 NM_032638.5 splice_region, intron
• Scores: Splicing: ADA: 0.005135
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.04

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 3-128481949-G-A is Benign according to our data. Variant chr3-128481949-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 412751.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA2	NM_032638.5	c.1018-5C>T		splice_region_variant, intron_variant	Intron 4 of 5	ENST00000341105.7	NP_116027.2
GATA2	NM_001145661.2	c.1018-5C>T		splice_region_variant, intron_variant	Intron 5 of 6		NP_001139133.1
GATA2	NM_001145662.1	c.1018-47C>T		intron_variant	Intron 4 of 5		NP_001139134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7	c.1018-5C>T		splice_region_variant, intron_variant	Intron 4 of 5	1	NM_032638.5	ENSP00000345681.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152176 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248826 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135006

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460842 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726706

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: 0.000116

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152176 Hom.: 1 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74332

Gnomad4 AFR AF: 0.00

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: 0.00

Gnomad4 OTH AF: 0.000955

Bravo AF: 0.00000756

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1018-5C>T intronic variant results from a C to T substitution 5 nucleotides upstream from coding exon 4 in the GATA2 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, the clinical significance of this variant remains unclear. -

not provided Uncertain:1

Mar 17, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge -

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0051
dbscSNV1_RF	Benign	0.026
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: rs769196688; hg19: chr3-128200792;