rs587776456

Positions:

• chrX-48794162-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The ENST00000376670.9(GATA1):​c.1240T>C​(p.Ter414ArgextTer41) 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 ENST00000376670.9 stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 4.04

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in ENST00000376670.9 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 id is 156270.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.1240T>C	p.Ter414ArgextTer41	stop_lost	6/6	ENST00000376670.9	NP_002040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA1	ENST00000376670.9	c.1240T>C	p.Ter414ArgextTer41	stop_lost	6/6	1	NM_002049.4	ENSP00000365858	P4

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

Likely pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
not provided, no classification provided	literature only	GeneReviews	-	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

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776456; hg19: chrX-48652569;