X-48791328-AG-A
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM2PP3_ModeratePP5_Moderate
The NM_002049.4(GATA1):c.220+1del variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Consequence
GATA1
NM_002049.4 frameshift, splice_region
NM_002049.4 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.26
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant X-48791328-AG-A is Pathogenic according to our data. Variant chrX-48791328-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 31942.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-48791328-AG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GATA1 | NM_002049.4 | c.220+1del | frameshift_variant, splice_region_variant | 2/6 | ENST00000376670.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GATA1 | ENST00000376670.9 | c.220+1del | frameshift_variant, splice_region_variant | 2/6 | 1 | NM_002049.4 | P4 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
X-linked dyserythropoetic anemia with abnormal platelets and neutropenia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 02, 2012 | - - |
Diamond-Blackfan anemia;C1845837:GATA binding protein 1 related thrombocytopenia with dyserythropoiesis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 07, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in GATA1 are known to be pathogenic (PMID: 16783379, 22706301, 23704091, 24453067). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of Diamond-Blackfan anemia (PMID: 22706301). This variant is also known as c.220+1del. ClinVar contains an entry for this variant (Variation ID: 31942). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Val74Serfs*63) in the GATA1 gene. It is expected to result in an absent or disrupted protein product. - |
Thrombocytopenia, X-linked, with or without dyserythropoietic anemia Other:1
not provided, no classification provided | literature only | GeneReviews | - | Exon skipping and frameshift are predicted because the deletion affects the canonic splice donor site. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at