rs587776452

Variant names:

• chrX-48791329-G-A
• rs587776452
• NM_002049.4:c.220G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-48791329-G-A
• chrX-48791329-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_002049.4(GATA1):​c.220G>A​(p.Val74Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V74L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GATA1 NM_002049.4 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 2.26
• Publications: 0 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-48791329-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 156266.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant X-48791329-G-A is Pathogenic according to our data. Variant chrX-48791329-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3377318.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA1	NM_002049.4	c.220G>A	p.Val74Ile	missense_variant, splice_region_variant	Exon 2 of 6	ENST00000376670.9	NP_002040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA1	ENST00000376670.9	c.220G>A	p.Val74Ile	missense_variant, splice_region_variant	Exon 2 of 6	1	NM_002049.4	ENSP00000365858.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Aug 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GATA1 c.220G>A; p.Val74Ile variant (rs587776452) to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 156266). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this missense variant is neutral or deleterious (REVEL: 0.417). However, this variant occurs at the last nucleotide of exon 2, and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the canonical donor splice site. Additionally, another variant at this nucleotide, c.220G>C; p.Val74Leu, is reported in individuals and families affected with features of Diamond-Blackfan anemia including macrocytic anemia, low reticulocyte counts, erythroid hypoplasia, and modest elevation of fetal hemoglobin, and is considered pathogenic (Hollanda 2006, Klar 2014, Sankaran 2012, Ulirsch 2018). Functional assays of the c.220G>C; p.Val74Leu variant demonstrate exon 2 skipping, leading to production of the short form GATA-1s mRNA (Hollanda 2006, Sankaran 2012). Notably, somatic GATA1 variants leading to this short form GATA-1s mRNA in patients with Down syndrome develop transient myeloproliferative disorder and may result in acute megakaryoblastic leukemia (Alford 2011, Wechsler 2002). Based on available information, the c.220G>A; p.Val74Ile variant is considered to be likely pathogenic. References: Alford KA et al. Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia. Blood. 2011 Aug 25;118(8):2222-38. PMID: 21715302. Hollanda LM et al. An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis. Nat Genet. 2006 Jul;38(7):807-12. PMID: 16783379. Klar J et al. Recurrent GATA1 mutations in Diamond-Blackfan anaemia. Br J Haematol. 2014 Sep;166(6):949-51. PMID: 24766296. Sankaran VG et al. Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J Clin Invest. 2012 Jul;122(7):2439-43. PMID: 22706301. Ulirsch JC et al. The Genetic Landscape of Diamond-Blackfan Anemia. Am J Hum Genet. 2018 Dec 6;103(6):930-947. PMID: 30503522. Wechsler J et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet. 2002 Sep;32(1):148-52. PMID: 12172547. -

X-linked dyserythropoetic anemia with abnormal platelets and neutropenia Uncertain:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. 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 valine to isoleucine. This variant affects the last nucleotide of the exon and has been referred as a splicing error variant (PMIDs: 20729467, 31606922). However, the splicing defect has not been functionally proven. The nucleotide is highly conserved but SpliceAI does not predict missplicing. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Val74Leu) has been reported in at least two families with males affected with Diamond-Blackfan anaemia (DBA; PMIDs: 22706301, 24766296) and one family with severe anaemia without thrombocytopenia (PMID: 16783379). Furthermore, RNA studies from affected individuals demonstrated exon 2 skipping. This variant has also been classified once as pathogenic in Clinvar. p.(Val74Phe) has also been reported in at least two individuals with Down Syndrome transient abnormal myelopoiesis (TAM), likely as a somatic variant (PMIDs: 20729467, 27353457). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. It has been reported in at least eleven individuals with acute myeloid leukemia of down syndrome (DS-AML). The somatic status of this variant was only confirmed in one of these individuals (PMID: 24056718). Bone marrow aspirates or cord blood were sample types used in analysis in the other ten individuals (PMIDs: 20729467, 24056718, 24196768, 25615715, 27353457, 31606922, 32681702, 37858167). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Mar 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 74 of the GATA1 protein (p.Val74Ile). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GATA1-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.220G nucleotide in the GATA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 16783397, 22706301, 24766296, 30503522). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	0.81	L;.
PhyloP100		2.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.37	N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.43	B;.
Vest4		0.30
MutPred		0.30		Loss of phosphorylation at Y69 (P = 0.2043);Loss of phosphorylation at Y69 (P = 0.2043);
MVP		0.66
MPC		0.047
ClinPred		0.34	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.35
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.45		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587776452; hg19: chrX-48649736; COSMIC: COSV64961668;