rs104894809

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216W) has been classified as Likely 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

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]

GATA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002049.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-48792370-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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
GATA1	NM_002049.4 link	c.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
GATA1	ENST00000376670.9 link	c.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:

AN:

111843

Hom.:

Cov.:

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:

AN:

1098046

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363406

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

26399

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

35205

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19383

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

30204

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

54134

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40522

Gnomad4 NFE exome

AF:

0.00000238

AC:

AN:

841983

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

46081

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111843

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34011

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000188

AC:

0.0000188356

AN:

0.0000188356

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000343

Hom.:

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

Nov 24, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

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

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

BayesDel_noAF

Pathogenic

0.73

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;D

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.5

H;.

PrimateAI

Uncertain

0.70

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

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.98

Mutation Taster

=22/78

disease causing (ClinVar)

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over