rs104894816

chrX-48792377-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_002049.4(GATA1):c.653A>G(p.Asp218Gly) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D218N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GATA1 NM_002049.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.47

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 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002049.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-48792376-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 627352.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant X-48792377-A-G is Pathogenic according to our data. Variant chrX-48792377-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA1	NM_002049.4	c.653A>G	p.Asp218Gly	missense_variant	4/6	ENST00000376670.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA1	ENST00000376670.9	c.653A>G	p.Asp218Gly	missense_variant	4/6	1	NM_002049.4	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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	-	- -

Thrombocytopenia, X-linked, without dyserythropoietic anemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

Thrombocytopenia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.71
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.84
MutPred		0.62		Gain of MoRF binding (P = 0.0155);Gain of MoRF binding (P = 0.0155);
MVP		1.0
MPC		2.1
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.98

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: rs104894816; hg19: chrX-48650784;