rs63750520
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The ENST00000251595.11(HBA2):c.420del(p.Lys140AsnfsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000343 in 1,459,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 26)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
HBA2
ENST00000251595.11 frameshift
ENST00000251595.11 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.21
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 Likely_pathogenic. Variant got 7 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-173588-CA-C is Pathogenic according to our data. Variant chr16-173588-CA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15629.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | c.420del | p.Lys140AsnfsTer9 | frameshift_variant | 3/3 | ENST00000251595.11 | NP_000508.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.420del | p.Lys140AsnfsTer9 | frameshift_variant | 3/3 | 1 | NM_000517.6 | ENSP00000251595 | P1 | |
HBA2 | ENST00000482565.1 | n.556del | non_coding_transcript_exon_variant | 2/2 | 1 | |||||
ENST00000702607.1 | n.72del | non_coding_transcript_exon_variant | 1/1 | |||||||
HBA2 | ENST00000397806.1 | c.324del | p.Lys108AsnfsTer9 | frameshift_variant | 3/3 | 2 | ENSP00000380908 |
Frequencies
GnomAD3 genomes Cov.: 26
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249094Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134916
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1459128Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 725630
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GnomAD4 genome Cov.: 26
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 01, 2023 | The HBA2 c.420del; p.Lys140AsnfsTer9 variant (Hb Wayne, also known as Lys139fs when numbered from the mature protein; rs63750520; HbVar ID: 702) has been reported in individuals with no clinical abnormalities (Salkie 1992, Seid-Akhavan 1976, HbVar database); however, its phenotype in the presence of other pathogenic globin variants is uncertain. The variant hemoglobin comprises 4-6% (Seid-Akhavan 1976) or 12-16% of total hemoglobin (Huisman 1984), depending on the purification methodology. Functional characterization of the variant hemoglobin indicates increased oxygen affinity and strong reduction in Bohr effect (Huisman 1984). The variant is listed in ClinVar (Variation ID: 15629) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The variant causes a frameshift that replaces the last three amino acids with eight novel amino acids at the C terminus. Although the variant causes protein translation past the canonical termination codon, it is not predicted to impact the downstream polyadenylation site (PolyA signal miner). Due to the limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Huisman T et al. Hb Wayne, the frameshift variant with extended alpha chains observed in a Caucasian family from Alabama. Hemoglobin. 1984; 8(1):1-15. PMID: 6327575. Salkie M et al. A Canadian family with Hb Wayne; characterization by HPLC and DNA sequencing. Hemoglobin. 1992; 16(6):515-9. PMID: 1487423. Seid-Akhavan M et al. Hemoglobin Wayne: a frameshift mutation detected in human hemoglobin alpha chains. Proc Natl Acad Sci U S A. 1976; 73(3):882-6. PMID: 1062801. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 20, 2016 | - - |
alpha Thalassemia Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 09, 2021 | - - |
HEMOGLOBIN WAYNE 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