rs1270810159
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_000517.6(HBA2):βc.69delβ(p.Glu24SerfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (β β ).
Frequency
Genomes: π 0.0 ( 0 hom., cov: 2)
Exomes π: 0.0000096 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
HBA2
NM_000517.6 frameshift
NM_000517.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -3.95
Genes affected
HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 6 pathogenic variants in the truncated region.
PP5
Variant 16-172980-GC-G is Pathogenic according to our data. Variant chr16-172980-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 439123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-172980-GC-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | c.69del | p.Glu24SerfsTer26 | frameshift_variant | 1/3 | ENST00000251595.11 | NP_000508.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.69del | p.Glu24SerfsTer26 | frameshift_variant | 1/3 | 1 | NM_000517.6 | ENSP00000251595 | P1 | |
HBA2 | ENST00000484216.1 | c.38del | p.Glu14SerfsTer26 | frameshift_variant | 1/2 | 1 | ENSP00000495899 | |||
HBA2 | ENST00000482565.1 | n.88del | non_coding_transcript_exon_variant | 1/2 | 1 | |||||
HBA2 | ENST00000397806.1 | c.-2+23del | intron_variant | 2 | ENSP00000380908 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 5238Hom.: 0 Cov.: 2 FAILED QC
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GnomAD3 exomes AF: 0.0000561 AC: 3AN: 53510Hom.: 0 AF XY: 0.0000742 AC XY: 2AN XY: 26968
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GnomAD4 exome AF: 0.00000956 AC: 4AN: 418318Hom.: 0 Cov.: 0 AF XY: 0.0000136 AC XY: 3AN XY: 219956
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GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 5238Hom.: 0 Cov.: 2 AF XY: 0.00 AC XY: 0AN XY: 2548
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 13, 2021 | This variant causes the premature termination of HBA2 protein synthesis, and has been reported in heterozygous carriers with mild microcytic anemia in the published literature (PMIDs: 16512835 (2006) and 17486494 (2007)). Functional studies showed that this variant does not affect RNA splicing, but the mRNA transcript is subject to nonsense-mediated decay (PMID: 16512835 (2006)). Therefore, the variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 23, 2022 | The HBA2 c.69delC; p.Glu24SerfsTer26 variant (rs1270810159), also known as codon 22 (-C), is reported in the literature in the heterozygous state in individuals with microcytic and hypochromic anemia (Luo 2007, Pereira 2006). This variant is also reported in ClinVar (Variation ID: 439123). This variant is found in the general population with an overall allele frequency of 0.006% (3/53510 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, and has been shown to result in a truncated mRNA subject to nonsense-mediated decay (Pereira 2006). Based on available information, this variant is considered to be pathogenic. References: Luo HY et al. Two new alpha-thalassemia frameshift mutations. Hemoglobin. 2007;31(2):135-9. PMID: 17486494. Pereira FJ et al. Human alpha2-globin nonsense-mediated mRNA decay induced by a novel alpha-thalassaemia frameshift mutation at codon 22. Br J Haematol. 2006 Apr;133(1):98-102. PMID: 16512835. - |
alpha Thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 20, 2019 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at