rs387907207

chrX-48792370-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_002049.4(GATA1):c.646C>T(p.Arg216Trp) variant causes a missense change involving the alteration of a non-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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GATA1 NM_002049.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:2
• Conservation: PhyloP100: 0.446

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]

ACMG classification

Verdict is Pathogenic. Variant got 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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant X-48792370-C-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA1	NM_002049.4	c.646C>T	p.Arg216Trp	missense_variant	4/6	ENST00000376670.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA1	ENST00000376670.9	c.646C>T	p.Arg216Trp	missense_variant	4/6	1	NM_002049.4	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GATA1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2023

The GATA1 c.646C>T variant is predicted to result in the amino acid substitution p.Arg216Trp. This variant was reported in three unrelated male individuals with congenital erythropoietic porphyria, with moderate thrombocytopenia with minimal or no anemia observed in some of the related carrier females (Phillips. 2007. PubMed ID: 17148589; Di Pierro. 2014. PubMed ID: 25251786). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 29, 2024

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26234528, 12200364, 19268002, 23704091, 28550189, 25251786, 17148589, 26392207) -

Beta-thalassemia-X-linked thrombocytopenia syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 15, 2007

- -

Cutaneous porphyria Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Thrombocytopenia, X-linked, with or without dyserythropoietic anemia Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
FATHMM_MKL	Benign	0.70	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.68
MutPred		0.93		Gain of catalytic residue at L214 (P = 0.0337);Gain of catalytic residue at L214 (P = 0.0337);
MVP		1.0
MPC		2.8
ClinPred		0.99	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
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

Other links and lift over

dbSNP: rs387907207; hg19: chrX-48650777;