rs104894809
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_002049.4(GATA1):c.647G>A(p.Arg216Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,209,889 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_002049.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000894 AC: 1AN: 111843Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34011
GnomAD4 exome AF: 0.00000182 AC: 2AN: 1098046Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 363406
GnomAD4 genome AF: 0.00000894 AC: 1AN: 111843Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34011
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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DNA sequence analysis of the GATA1 gene demonstrated a sequence change, c.647G>A, in exon 4 that results in an amino acid change, p.Arg216Gln. This sequence change has not been described in population databases such as ExAC and gnomAD (dbSNP rs104894809). The p.Arg216Gln change affects a highly conserved amino acid residue located in a domain of the GATA1 protein that is known to be functional. The p.Arg216Gln substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in several families with X-linked thrombocytopenia with thalassemia (PMID: 25421114, 12200364, 17209061, 11809723). The p.Arg216Gln amino acid change also occurs in a region of the GATA1 gene where other missense sequence changes have been described in individuals with GATA1-related thrombocytopenia (PMID: 25421114). A functional study demonstrated that the p.Arg216Gln change impairs recruitment of the TAL1 complex, impacting transcriptional activation (PMID: 23704091). Collectively, these evidences indicate that this sequence change pathogenic. -
Thrombocytopenia, X-linked, with or without dyserythropoietic anemia Pathogenic:2Other:1
Also reported in one family with "gray platelet syndrome". -
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X-linked dyserythropoetic anemia with abnormal platelets and neutropenia Pathogenic:1
ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM5 moderated, PP1 strong, PP3 supporting -
Diamond-Blackfan anemia;C1845837:GATA binding protein 1 related thrombocytopenia with dyserythropoiesis Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 216 of the GATA1 protein (p.Arg216Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thrombocytopenia (PMID: 12200364, 14691578, 17209061, 19172521). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10428). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GATA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GATA1 function (PMID: 12200364, 23704091). For these reasons, this variant has been classified as Pathogenic. -
Beta-thalassemia-X-linked thrombocytopenia syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at