rs587776451

chrX-48791111-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate 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

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 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_002049.4 (GATA1) was described as [Pathogenic] in ClinVar as 1068653
• 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 id is 156265.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-48791111-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA1	NM_002049.4	c.2T>C	p.Met1?	start_lost	2/6	ENST00000376670.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA1	ENST00000376670.9	c.2T>C	p.Met1?	start_lost	2/6	1	NM_002049.4	P4

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2014

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2023

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

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

not provided, no classification provided

literature only

GeneReviews

-

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
MutationTaster	Benign	1.0	D;D
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

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: rs587776451; hg19: chrX-48649518; COSMIC: COSV64963836;