X-48791144-C-G

Variant names:

• chrX-48791144-C-G
• rs2062673416
• NM_002049.4:c.35C>G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002049.4(GATA1):​c.35C>G​(p.Ser12*) variant causes a stop gained 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 (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: GATA1 NM_002049.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.49

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 53 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-48791144-C-G is Pathogenic according to our data. Variant chrX-48791144-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 952388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATA1	NM_002049.4	c.35C>G	p.Ser12*	stop_gained	Exon 2 of 6	ENST00000376670.9	NP_002040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATA1	ENST00000376670.9	c.35C>G	p.Ser12*	stop_gained	Exon 2 of 6	1	NM_002049.4	ENSP00000365858.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GATA1-related disorder Pathogenic:1

Sep 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GATA1 c.35C>G variant is predicted to result in premature protein termination (p.Ser12*). This variant located in exon 2 which was reported in two individuals with transient abnormal myelopoiesis (TAM) with Down syndrome (Chukua et al. 2019. PubMed ID: 31687255; Camargo et al. 2022. PubMed ID: 35731576). Acquired truncating GATA1 variants, particularly in exon 2, are known to be associated with transient myeloproliferative disorder and megakaryoblastic leukemia in children with Down syndrome (Hitzler et al. 2003. PubMed ID: 12586620; Rainis et al. 2003. PubMed ID: 12649131; Camargo et al. 2022. PubMed ID: 35731576). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/952388/). Nonsense variants in GATA1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Down syndrome;C1839161:Beta-thalassemia-X-linked thrombocytopenia syndrome;C3550789:Thrombocytopenia, X-linked, with or without dyserythropoietic anemia;C3550856:X-linked dyserythropoetic anemia with abnormal platelets and neutropenia Pathogenic:1

Jul 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 25, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loss-of-function variants in GATA1 are known to be pathogenic (PMID: 16783379, 22706301, 23704091, 24453067). This variant has not been reported in the literature in individuals with GATA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser12*) in the GATA1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	35
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.68	D
Vest4		0.75
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs2062673416; hg19: chrX-48649551; COSMIC: COSV64962292;