rs281864560
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM4_SupportingPP5_Very_Strong
The NM_000517.6(HBA2):βc.91_93delβ(p.Glu31del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.0 ( 0 hom., cov: 3)
Failed GnomAD Quality Control
Consequence
HBA2
NM_000517.6 inframe_deletion
NM_000517.6 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.984
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 11 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000517.6
PM4
?
Nonframeshift variant in NON repetitive region in NM_000517.6. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 16-173001-TGGA-T is Pathogenic according to our data. Variant chr16-173001-TGGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | c.91_93del | p.Glu31del | inframe_deletion | 1/3 | ENST00000251595.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.91_93del | p.Glu31del | inframe_deletion | 1/3 | 1 | NM_000517.6 | P1 | |
HBA2 | ENST00000484216.1 | c.60_62del | p.Glu21del | inframe_deletion | 1/2 | 1 | |||
HBA2 | ENST00000482565.1 | n.110_112del | non_coding_transcript_exon_variant | 1/2 | 1 | ||||
HBA2 | ENST00000397806.1 | c.-2+45_-2+47del | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 9042Hom.: 0 Cov.: 3 FAILED QC
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We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 9042Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0AN XY: 4192
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 08, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 12, 2023 | The HBA2 c.91_93delGAG; p.Glu31del variant (also known as codon 30 (-GAG) or as Glu30del when numbered from the mature protein, rs281864560, HbVar ID: 2776) is reported in the literature in multiple individuals affected with Hb H disease in trans to large deletions of HBA1 and HBA2 (Chan 1997, Chen 2000, Yang 2013). The p.Glu31del variant is also reported in heterozygous individuals with mild microcytosis and hypochromia (Yang 2013, HbVar database). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single glutamate residue, leaving the rest of the protein in-frame. Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Chan V et al. Molecular defects in Hb H hydrops fetalis. Br J Haematol. 1997 Feb;96(2):224-8. PMID: 9029003. Chen FE et al. Genetic and clinical features of hemoglobin H disease in Chinese patients. N Engl J Med. 2000 Aug 24;343(8):544-50. PMID: 10954762. Yang Y and Li DZ. CODON 30 (-GAG) (a2): hematological parameters in heterozygotes and also patients with Hb H disease. Hemoglobin. 2013;37(6):599-603. PMID: 23822871. - |
HEMOGLOBIN H HYDROPS FETALIS SYNDROME Other:1
other, no assertion criteria provided | literature only | OMIM | Sep 12, 2022 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at