rs63750010
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BS2_Supporting
The NM_000517.6(HBA2):c.326C>A(p.Thr109Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000473 in 1,606,354 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000517.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000338 AC: 5AN: 147818Hom.: 0 Cov.: 25
GnomAD3 exomes AF: 0.0000768 AC: 19AN: 247506Hom.: 1 AF XY: 0.0000893 AC XY: 12AN XY: 134342
GnomAD4 exome AF: 0.0000487 AC: 71AN: 1458424Hom.: 8 Cov.: 33 AF XY: 0.0000744 AC XY: 54AN XY: 725324
GnomAD4 genome AF: 0.0000338 AC: 5AN: 147930Hom.: 0 Cov.: 25 AF XY: 0.0000554 AC XY: 4AN XY: 72264
ClinVar
Submissions by phenotype
not provided Uncertain:3
The HBA2 c.326C>A; p.Thr109Asn variant (Hb Bleuland also known as Thr108Asn when numbered from the mature protein, rs63750010, HbVar ID: 2539) is reported in the literature in the heterozygous state in individuals with mild microcytic-hypochromic anemia (Hadavi 2009, Harteveld 2006, Tamaddoni 2009). This variant is also reported in ClinVar (Variation ID: 439114), and is found in the South Asian population with an allele frequency of 0.063% (19/30264 alleles, including a single homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.536). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Hadavi V et al. Alpha-thalassemia mutations in Gilan Province, North Iran. Hemoglobin. 2009;33(3):235-41. PMID: 19657838. Harteveld CL et al. Hb Bleuland (alpha108(G15)Thr-->Asn, ACC-->AAC (alpha2)): a new abnormal hemoglobin associated with a mild alpha-thalassemia phenotype. Hemoglobin. 2006;30(3):349-54. PMID: 16840225. Tamaddoni A et al. alpha-Thalassemia mutation analyses in Mazandaran province, North Iran. Hemoglobin. 2009;33(2):115-23. PMID: 19373587. -
- -
The HBA2 c.326C>A (p.Thr109Asn, also known as Hb Bleuland) variant has been reported in the published literature to be hyper unstable (PMID: 25730315 (2015)) and heterozygosity for this variant is associated with mild hemolytic anemia (PMID: 24200101 (2014)). Individuals heterozygous for this variant have a mild alpha-thalassemia phenotype (PMID: 16840225 (2006), 19373587 (2009)). The frequency of this variant in the general population, 0.00063 (19/30264 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
not specified Uncertain:1
Variant summary: HBA2 c.326C>A (p.Thr109Asn), also referred to as Hb Bleuland, results in a non-conservative amino acid change located in the globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 247506 control chromosomes, predominantly at a frequency of 0.00063 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in HBA2 causing Alpha Thalassemia (7.7e-05 vs 0.0056), allowing no strong conclusion about variant significance. c.326C>A has been reported in the literature in the heterozygous state in at least two individuals affected with mild microcytic-hypochromic anemia (e.g. Harteveld_2006, Hadavi_2009, Tamaddoni_2009). These reports do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. A functional study examining the interaction between the variant and alpha-hemoglobin stabilizing protein found that the variant was recovered with the chaperone at a similar level as the WT protein, suggesting the interaction is normal (Vasseur_2009). However, this study does not address other potential mechanisms that may have an impact on protein stability and/or function and therefore does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 19657838, 16840225, 19373587, 19482015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely pathogenic or uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at