rs587776451

Variant names:

• chrX-48791111-T-C
• rs587776451
• NM_002049.4:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002049.4(GATA1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GATA1 NM_002049.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 2.81
• Publications: 9 publications found

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]

GATA1 Gene-Disease associations (from GenCC):

• GATA1-Related X-Linked Cytopenia

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• thrombocytopenia, X-linked, with or without dyserythropoietic anemia

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• beta-thalassemia-X-linked thrombocytopenia syndrome

  Inheritance: XL Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cutaneous porphyria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thrombocytopenia with congenital dyserythropoietic anemia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked dyserythropoetic anemia with abnormal platelets and neutropenia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000232828 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 50 pathogenic variants. Next in-frame start position is after 84 codons. Genomic position: 48791873. Lost 0.201 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-48791111-T-C is Pathogenic according to our data. Variant chrX-48791111-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 156265.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA1	NM_002049.4	c.2T>C	p.Met1?	start_lost	Exon 2 of 6	ENST00000376670.9	NP_002040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA1	ENST00000376670.9	c.2T>C	p.Met1?	start_lost	Exon 2 of 6	1	NM_002049.4	ENSP00000365858.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked dyserythropoetic anemia with abnormal platelets and neutropenia Pathogenic:1

Jul 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Feb 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that disruption of the initiator codon affects GATA1 function (PMID: 20729467, 24952648). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 156265). Disruption of the initiator codon has been observed in individual(s) with Diamond-Blackfan anemia (PMID: 24453067, 24952648, 29146883). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the GATA1 mRNA. The next in-frame methionine is located at codon 84. For these reasons, this variant has been classified as Pathogenic. -

Thrombocytopenia, X-linked, with or without dyserythropoietic anemia Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Obliterates initiation codon; alternative initiation Met84 residue is used, resulting in lack of full length cDNA -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.32	T;T
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.58	D
PhyloP100		2.8
PROVEAN	Benign	-0.060	N;N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.055	B;.
Vest4		0.93
MutPred		0.61		Gain of glycosylation at M1 (P = 0.0053);Gain of glycosylation at M1 (P = 0.0053);
MVP		0.98
ClinPred		0.77	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.84
gMVP		0.68
Mutation Taster		=16/184	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776451; hg19: chrX-48649518;