Genetic Variant GATA2:c.1018-226T>G (chr3-128482170-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032638.5(GATA2):c.1018-226T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 599,928 control chromosomes in the GnomAD database, including 14,978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4195 hom., cov: 33)

Exomes 𝑓: 0.21 ( 10783 hom. )

Consequence

GATA2
NM_032638.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0550

Publications

5 publications found

Variant links:

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

GATA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 3-128482170-A-C is Benign according to our data. Variant chr3-128482170-A-C is described in ClinVar as Benign. ClinVar VariationId is 1277301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GATA2	NM_032638.5 link	c.1018-226T>G	intron_variant	Intron 4 of 5	ENST00000341105.7	NP_116027.2	P23769-1
GATA2	NM_001145661.2 link	c.1018-226T>G	intron_variant	Intron 5 of 6		NP_001139133.1	P23769-1
GATA2	NM_001145662.1 link	c.1018-268T>G	intron_variant	Intron 4 of 5		NP_001139134.1	P23769-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA2	ENST00000341105.7 link	c.1018-226T>G		intron_variant	Intron 4 of 5	1	NM_032638.5	ENSP00000345681.2		P23769-1

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

35021

AN:

152082

Hom.:

4192

Cov.:

show subpopulations

Gnomad AFR

AF:

0.253

Gnomad AMI

AF:

0.324

Gnomad AMR

AF:

0.224

Gnomad ASJ

AF:

0.178

Gnomad EAS

AF:

0.134

Gnomad SAS

AF:

0.0997

Gnomad FIN

AF:

0.209

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.233

GnomAD4 exome

AF:

0.212

AC:

95002

AN:

447728

Hom.:

10783

AF XY:

0.206

AC XY:

48139

AN XY:

234070

show subpopulations

African (AFR)

AF:

0.250

AC:

3063

AN:

12258

American (AMR)

AF:

0.225

AC:

4012

AN:

17800

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

2501

AN:

13194

East Asian (EAS)

AF:

0.132

AC:

3884

AN:

29316

South Asian (SAS)

AF:

0.105

AC:

4714

AN:

44832

European-Finnish (FIN)

AF:

0.211

AC:

5693

AN:

26958

Middle Eastern (MID)

AF:

0.229

AC:

433

AN:

1890

European-Non Finnish (NFE)

AF:

0.235

AC:

64956

AN:

275986

Other (OTH)

AF:

0.225

AC:

5746

AN:

25494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

3459

6918

10378

13837

17296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

526

1052

1578

2104

2630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.230

AC:

35046

AN:

152200

Hom.:

4195

Cov.:

AF XY:

0.226

AC XY:

16849

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.253

AC:

10488

AN:

41516

American (AMR)

AF:

0.223

AC:

3418

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.178

AC:

619

AN:

3468

East Asian (EAS)

AF:

0.133

AC:

691

AN:

5180

South Asian (SAS)

AF:

0.101

AC:

486

AN:

4832

European-Finnish (FIN)

AF:

0.209

AC:

2211

AN:

10596

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.239

AC:

16274

AN:

67986

Other (OTH)

AF:

0.230

AC:

486

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1403

2806

4208

5611

7014

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

348

696

1044

1392

1740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.235

Hom.:

3793

Bravo

AF:

0.236

Asia WGS

AF:

0.133

AC:

465

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

3.2

(source)

DANN

Benign

0.77

PhyloP100

0.055

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over