X-48792377-A-G

Position:

• chrX-48792377-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 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 (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GATA1 NM_002049.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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	Protein	UniProt
GATA1	NM_002049.4	c.653A>G	p.Asp218Gly	missense_variant	4/6	ENST00000376670.9	NP_002040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATA1	ENST00000376670.9	c.653A>G	p.Asp218Gly	missense_variant	4/6	1	NM_002049.4	ENSP00000365858.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thrombocytopenia, X-linked, with or without dyserythropoietic anemia Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 10, 2024	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with GATA1-related X-linked cytopenia (MONDO#0100089). (I) 0109 - This gene is associated with X-linked disease. Although males are more severely affected, females can have a milder phenotype, composed of mild anaemia and thrombocytopenia (PMID: 33611093). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glycine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Asp218Asn) has been reported in individuals with macrothrombocytopenia (ClinVar, PMIDs: 23971719, 11809723). p.(Asp218Tyr) has been reported in individuals with severe macrothrombocytopenia, marked anaemia and early mobility, however, it is not considered comparable as it has a higher Grantham score, indicating a greater physicochemical difference (ClinVar, PMIDs: 11809723, 31652397). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported in a large family with X-linked macrothrombocytopenia with no marked anaemia (PMID: 11418466). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate with disease in a large family with X-linked macrothrombocytopenia with no marked anaemia (PMID: 11418466). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies on patient platelets has shown that the binding between GATA1 and FOG1 is reduced (PMID: 12483298). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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;.
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;