X-48791128-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002049.4(GATA1):c.19G>C(p.Gly7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000896 in 111,616 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
• Consequence: GATA1 NM_002049.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.82

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37318414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATA1	NM_002049.4	c.19G>C	p.Gly7Arg	missense_variant	2/6	ENST00000376670.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATA1	ENST00000376670.9	c.19G>C	p.Gly7Arg	missense_variant	2/6	1	NM_002049.4	P4

Frequencies

GnomAD3 genomes AF: 0.00000896 AC: 1 AN: 111565 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33767

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: 0.00420

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000896 AC: 1 AN: 111616 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33828

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

Mar 13, 2022

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with GATA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 7 of the GATA1 protein (p.Gly7Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.94	N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.98	D;.
Vest4		0.40
MutPred		0.23		Gain of methylation at G7 (P = 0.0247);Gain of methylation at G7 (P = 0.0247);
MVP		0.71
MPC		0.33
ClinPred		0.69	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.30
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-48649535;