rs587776456

Variant names:

• chrX-48794162-T-C
• rs587776456
• NM_002049.4:c.1240T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_002049.4(GATA1):​c.1240T>C​(p.Ter414Argext*?) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GATA1 NM_002049.4 stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 4.04
• Publications: 5 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_002049.4 Downstream stopcodon found after 438 codons.
• PP5: Variant X-48794162-T-C is Pathogenic according to our data. Variant chrX-48794162-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 156270.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.1240T>C	p.Ter414Argext*?	stop_lost	Exon 6 of 6	ENST00000376670.9	NP_002040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA1	ENST00000376670.9	c.1240T>C	p.Ter414Argext*?	stop_lost	Exon 6 of 6	1	NM_002049.4	ENSP00000365858.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

-

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Pathogenic variant in stop codon 414 results in addition of 41 amino acids and use of new stop codon at residue 42 -

Thrombocytopenia Pathogenic:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	15
DANN	Benign	0.80
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.18	T
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.0	T
PhyloP100		4.0
PROVEAN	Benign	-0.52	N
REVEL	Uncertain	0.34
Sift	Benign	0.057	T
Sift4G	Benign	0.064	T
Vest4		0.74
MutPred		0.33		Gain of phosphorylation at M300 (P = 0.0471);
MVP		0.85
ClinPred		0.25	T
GERP RS		3.9
Mutation Taster		=23/177	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587776456; hg19: chrX-48652569;