rs1557020001

Positions:

• chrX-48791126-TG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_002049.4(GATA1):​c.21del​(p.Ser8ProfsTer129) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GATA1 NM_002049.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.164

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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.986 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-48791126-TG-T is Pathogenic according to our data. Variant chrX-48791126-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 465133.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATA1	NM_002049.4	c.21del	p.Ser8ProfsTer129	frameshift_variant	2/6	ENST00000376670.9	NP_002040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA1	ENST00000376670.9	c.21del	p.Ser8ProfsTer129	frameshift_variant	2/6	1	NM_002049.4	ENSP00000365858	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diamond-Blackfan anemia;C1845837:GATA binding protein 1 related thrombocytopenia with dyserythropoiesis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2017

For these reasons, this variant has been classified as Pathogenic. This variant is expected to result in a truncated GATA1 protein that lacks the N-terminal zinc-finger (residues 198-233) and C-terminal zinc-finger (residues 254-286). These domains mediate not only DNA binding, but also the majority of protein-protein interactions required for the proper transcriptional regulatory function of the GATA1 protein (PMID: 11566888, 16095949, 8628290, 15920471, 24255919). Several missense variants that result in disrupted function of the GATA1 protein have been reported in individuals affected with GATA1-related disease, indicating that loss-of-function variants in GATA1 are pathogenic (PMID: 23704091). This variant has not been reported in the literature in individuals with GATA1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser8Profs*129) in the GATA1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs1557020001; hg19: chrX-48649533;