X-48791089-A-G

Position:

• chrX-48791089-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_002049.4(GATA1):​c.-19-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GATA1 NM_002049.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.08

Genes affected

GATA1 (HGNC:4170): (GATA binding protein 1) This gene encodes a protein which belongs to the GATA family of transcription factors. The protein plays an important role in erythroid development by regulating the switch of fetal hemoglobin to adult hemoglobin. Mutations in this gene have been associated with X-linked dyserythropoietic anemia and thrombocytopenia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.19162641 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.6, offset of 12, new splice context is: cctcgcgggttaatccccAGagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-48791089-A-G is Pathogenic according to our data. Variant chrX-48791089-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 3344400.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA1	NM_002049.4	c.-19-2A>G		splice_acceptor_variant		ENST00000376670.9	NP_002040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA1	ENST00000376670.9	c.-19-2A>G		splice_acceptor_variant		1	NM_002049.4	ENSP00000365858	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1060340 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 333432

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

GATA1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2024

The GATA1 c.-19-2A>G variant is located in the 5' untranslated region. This variant (also described as c.-21A>G) has been reported in the hemizygous state in an individual with dyserythropoietic anemia, thrombocytosis, functional platelet defect, and megakaryocyte dysplasia (Zucker et al. 2016. PubMed ID: 26713410). It has also been reported in a father (hemi) and daughter (het) with myelodysplastic syndrome (MDS) (Table S1, Hasle et al. 2022. PubMed ID: 34758059) and in an unrelated sibling pair where the brother (hemi) and sister (het) were affected with hypoplastic bone marrow and primary myelofibrosis, respectively (Molteni et al. 2023. PubMed ID: 37216690). Consistent with in silico splicing predictions (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), transcriptional analysis of patient bone marrow cells confirmed that the c.-19-2G>A variant disrupts the canonical acceptor site, leading to exon 2 skipping and reduced production of the full-length GATA1 protein required for proper hematopoiesis in erythrocyte and megakaryocyte precursors (Zucker et al. 2016. PubMed ID: 26713410). This variant has not been reported in the gnomAD database, indicating this variant is rare. However, a different nucleotide change disrupting the same canonical acceptor site (c.-19-1G>A) has been observed in individuals with GATA1-related phenotypes tested at PreventionGenetics (internal data). Taken together, the c.-19-2A>G variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	27
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: 14
DS_AL_spliceai		0.98		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-48649496; COSMIC: COSV64961674;