3-128486223-T-G

Variant names:

• chr3-128486223-T-G
• rs763281230
• NM_001145661.2:c.375A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001145661.2(GATA2):​c.375A>C​(p.Pro125Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,408,634 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 Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: GATA2 NM_001145661.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.916
• Publications: 0 publications found

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]

GATA2 Gene-Disease associations (from GenCC):

• deafness-lymphedema-leukemia syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• GATA2 deficiency with susceptibility to MDS/AML

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• monocytopenia with susceptibility to infections

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• myelodysplastic syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-128486223-T-G is Benign according to our data. Variant chr3-128486223-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 412750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.916 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000185 (26/1408634) while in subpopulation MID AF = 0.00308 (17/5528). AF 95% confidence interval is 0.00196. There are 0 homozygotes in GnomAdExome4. There are 13 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 26 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145661.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA2	NM_001145661.2	MANE Plus Clinical	c.375A>C	p.Pro125Pro	synonymous	Exon 4 of 7	NP_001139133.1
	GATA2	NM_032638.5	MANE Select	c.375A>C	p.Pro125Pro	synonymous	Exon 3 of 6	NP_116027.2
	GATA2	NM_001145662.1		c.375A>C	p.Pro125Pro	synonymous	Exon 3 of 6	NP_001139134.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATA2	ENST00000341105.7	TSL:1 MANE Select	c.375A>C	p.Pro125Pro	synonymous	Exon 3 of 6	ENSP00000345681.2
	GATA2	ENST00000487848.6	TSL:1 MANE Plus Clinical	c.375A>C	p.Pro125Pro	synonymous	Exon 4 of 7	ENSP00000417074.1
	GATA2	ENST00000430265.6	TSL:1	c.375A>C	p.Pro125Pro	synonymous	Exon 3 of 6	ENSP00000400259.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000803 AC: 13 AN: 161834 AF XY: 0.0000695

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000799

Gnomad OTH exome AF: 0.00178

GnomAD4 exome AF: 0.0000185 AC: 26 AN: 1408634 Hom.: 0 Cov.: 36 AF XY: 0.0000187 AC XY: 13 AN XY: 695426

African (AFR) AF: 0.00 AC: 0 AN: 32728

American (AMR) AF: 0.00 AC: 0 AN: 36036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25240

East Asian (EAS) AF: 0.00 AC: 0 AN: 37332

South Asian (SAS) AF: 0.00 AC: 0 AN: 80284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48500

Middle Eastern (MID) AF: 0.00308 AC: 17 AN: 5528

European-Non Finnish (NFE) AF: 0.00000369 AC: 4 AN: 1084554

Other (OTH) AF: 0.0000856 AC: 5 AN: 58432

GnomAD4 genome Cov.: 32

Alfa AF: 0.000610 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Deafness-lymphedema-leukemia syndrome;C3280030:Monocytopenia with susceptibility to infections (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.0
DANN	Benign	0.74
PhyloP100		-0.92

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

Other links and lift over

dbSNP: rs763281230; hg19: chr3-128205066;