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

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

GATA1
NM_002049.4 missense

Scores

13
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 8.13
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant X-48792371-G-A is Pathogenic according to our data. Variant chrX-48792371-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48792371-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GATA1NM_002049.4 linkc.647G>A p.Arg216Gln missense_variant Exon 4 of 6 ENST00000376670.9 NP_002040.1 P15976-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GATA1ENST00000376670.9 linkc.647G>A p.Arg216Gln missense_variant Exon 4 of 6 1 NM_002049.4 ENSP00000365858.3 P15976-1

Frequencies

GnomAD3 genomes
AF:
0.00000894
AC:
1
AN:
111843
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34011
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000182
AC:
2
AN:
1098046
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
363406
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000238
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000894
AC:
1
AN:
111843
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
34011
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 01, 2021
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

Also reported in one family with "gray platelet syndrome". -

Nov 24, 2023
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

X-linked dyserythropoetic anemia with abnormal platelets and neutropenia Pathogenic:1
Mar 15, 2022
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jun 01, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Oct 01, 2007
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.67
D
BayesDel_noAF
Pathogenic
0.73
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
1.0
D;D
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Pathogenic
4.5
H;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-3.9
D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.88
MutPred
0.91
Loss of MoRF binding (P = 0.0452);Loss of MoRF binding (P = 0.0452);
MVP
1.0
MPC
2.7
ClinPred
1.0
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.96
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs104894809; hg19: chrX-48650778; COSMIC: COSV64962346; API