X-48791103-AGGCTCCATGGAGTTCCCTGGCCTGG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002049.4(GATA1):c.-4_21del variant causes a start lost, 5 prime UTR change. 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 start_lost, 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.28

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-48791103-AGGCTCCATGGAGTTCCCTGGCCTGG-A is Pathogenic according to our data. Variant chrX-48791103-AGGCTCCATGGAGTTCCCTGGCCTGG-A is described in ClinVar as [Pathogenic]. Clinvar id is 2952845.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA1	NM_002049.4	c.-4_21del		start_lost, 5_prime_UTR_variant	2/6	ENST00000376670.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA1	ENST00000376670.9	c.-4_21del		start_lost, 5_prime_UTR_variant	2/6	1	NM_002049.4	P4

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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

Invitae

Oct 14, 2023

This sequence change affects the initiator methionine of the GATA1 mRNA. The next in-frame methionine is located at codon 1. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GATA1-related conditions. This variant disrupts a region of the GATA1 protein in which other variant(s) (p.Met1?) have been determined to be pathogenic (PMID: 24453067, 24952648, 29146883, 35328001; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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-48649510;