rs997764249

chrX-48792042-G-AchrX-48792042-G-CchrX-48792042-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_002049.4(GATA1):c.419G>A(p.Arg140Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 1,210,040 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R140W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 4 hem.)
• Consequence: GATA1 NM_002049.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.54

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27178556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA1	NM_002049.4	c.419G>A	p.Arg140Gln	missense_variant	3/6	ENST00000376670.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA1	ENST00000376670.9	c.419G>A	p.Arg140Gln	missense_variant	3/6	1	NM_002049.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111853 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34043

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: 0.0000189

Gnomad OTH AF: 0.000664

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183417 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67861

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000127 AC: 14 AN: 1098187 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 4 AN XY: 363561

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111853 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34043

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: 0.0000189

Gnomad4 OTH AF: 0.000664

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diamond-Blackfan anemia;C1845837:GATA binding protein 1 related thrombocytopenia with dyserythropoiesis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 16, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with GATA1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 140 of the GATA1 protein (p.Arg140Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 22, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	23
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.97	N;N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.081	T;T
Polyphen		0.99	D;.
Vest4		0.31
MutPred		0.22		Loss of phosphorylation at S142 (P = 0.0856);Loss of phosphorylation at S142 (P = 0.0856);
MVP		0.85
MPC		0.29
ClinPred		0.73	D
GERP RS		4.6
Varity_R		0.45
gMVP		0.61

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: rs997764249; hg19: chrX-48650449;