rs104894816

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_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

Scores

10
5
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 7.47
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
GATA1NM_002049.4 linkuse as main transcriptc.653A>G p.Asp218Gly missense_variant 4/6 ENST00000376670.9 NP_002040.1 P15976-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GATA1ENST00000376670.9 linkuse as main transcriptc.653A>G p.Asp218Gly missense_variant 4/61 NM_002049.4 ENSP00000365858.3 P15976-1

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
22

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Thrombocytopenia, X-linked, with or without dyserythropoietic anemia Pathogenic:2Other:1
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, criteria provided, single submitterclinical testingISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology-- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteOct 10, 2024Based 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 providedliterature onlyOMIMJul 01, 2001- -
Thrombocytopenia Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchNIHR Bioresource Rare Diseases, University of CambridgeFeb 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104894816; hg19: chrX-48650784; API