rs281864566
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5
The NM_000558.5(HBA1):c.98T>A(p.Met33Lys) variant causes a missense, splice region 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. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M33I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000558.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA1 | NM_000558.5 | c.98T>A | p.Met33Lys | missense_variant, splice_region_variant | 2/3 | ENST00000320868.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA1 | ENST00000320868.9 | c.98T>A | p.Met33Lys | missense_variant, splice_region_variant | 2/3 | 1 | NM_000558.5 | P1 | |
HBA1 | ENST00000472694.1 | n.234T>A | non_coding_transcript_exon_variant | 1/2 | 1 | ||||
HBA1 | ENST00000487791.1 | n.67T>A | splice_region_variant, non_coding_transcript_exon_variant | 2/2 | 1 | ||||
HBA1 | ENST00000397797.1 | c.2T>A | p.Met1? | start_lost, splice_region_variant | 2/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD4 exome Cov.: 13
GnomAD4 genome ? Cov.: 30
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 26, 2021 | The Hb Queens Park variant (HBA1: c.98T>A; p.Met33Lys, also known as Met32Lys when numbered from the mature protein, rs281864566) is reported in the literature in an individual with microcytic anemia who also carries the –alpha3.7 deletion (Phylipsen 2010, see HbVar Hb Queens Park link). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 33 is highly conserved, and computational analyses (REVEL: 0.835) predict that this variant is deleterious. Additionally, variants at this residue occur in a region important for alpha-beta globin contacts and are not usually detected by HPLC and thus are considered unstable (Brennan 2017, Harteveld 2005). Furthermore, a different variant at this codon (p.Met33Ile) is reported in individuals with microcytic anemia and is considered to be disease-causing (Brennan 2017, Harteveld 2005, see HbVar Hb Amsterdam-A1 link). Based on available information, the Hb Queens Park variant is considered to be pathogenic. References: HbVar link to Hb Amsterdam-A1: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=3126&.cgifields=histD HbVar link to Hb Queens Park: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=2784&.cgifields=histD Brennan SO et al. Hb Amsterdam-A1 (a32(B13)Met?Ile; HBA1: c.99G>A): A Hyperunstable Variant Due to a New Mutation on the a1 Gene. Hemoglobin. 2017 Mar;41(2):140-143. Harteveld CL et al. Hb Amsterdam (alpha32(B13)Met--Ile (alpha2)): a new unstable variant associated with an alpha-thalassemia phenotype and a new African polymorphism. Hemoglobin. 2005;29(4):257-62. Phylipsen M et al. Two new alpha1-globin gene point mutations: Hb Nedlands (HBA1:c.86C>T) (alpha28(B9)Ala-->Val) and Hb Queens Park (HBA1:c.98T>A) (alpha32(B13)Met-->Lys). Hemoglobin. 2010 Jan;34(2):123-6. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 25, 2023 | Variant summary: HBA1 c.98T>A (p.Met33Lys), also referred to as Hb Queens Park, results in a non-conservative amino acid change located in the globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant is also located near a canonical splice site and therefore could have an impact on normal RNA splicing: three computational tools predict the variant has no significant impact on splicing, whereas one predicts the variant slightly weakens the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 129824 control chromosomes (gnomAD). c.98T>A has been reported in the literature in two individuals together with the --SEA deletion, who were affected with a moderate microcytic-hypochromic anemia, and were positive for HbH inclusion bodies (Sroymora_2012, Viprakasit_2014), consistent with a (mild) HbH disease. In addition, the variant was also reported in trans with the -a3.7 deletion, in an individual who was affected with a mild microcytic-hypochromic anemia, without HbH inclusion bodies (Phylipsen_2010); this clinical picture is compatible with an alpha thalassemia trait (alpha thalassemia minor). Finally, the variant was also reported in silent carriers (He_2017, Tan_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating this impact on protein function has been reported, however it has been suggested that the variant might result in an unstable protein, due to disrupting an amino acid that is important for alpha-beta globin contacts (Phylipsen_2010) or heme contact (Brennan_2017). In addition, other variants affecting the same amino acid (Met33Ile/Thr) have been reported in affected individuals (HGMD). The following publications have been ascertained in the context of this evaluation (PMID: 20353346, 22384838, 33439495, 24081251, 28125089, 28696843). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at