chr16-173512-TC-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000517.6(HBA2):c.345del(p.Ala116ProfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000203 in 147,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 25)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
HBA2
NM_000517.6 frameshift
NM_000517.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0440
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 18 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 22 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-173512-TC-T is Pathogenic according to our data. Variant chr16-173512-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 439116.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.345del | p.Ala116ProfsTer18 | frameshift_variant | 3/3 | ENST00000251595.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.345del | p.Ala116ProfsTer18 | frameshift_variant | 3/3 | 1 | NM_000517.6 | P1 | |
ENST00000702607.1 | n.148del | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes AF: 0.0000203 AC: 3AN: 147694Hom.: 0 Cov.: 25
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GnomAD3 exomes AF: 0.00000811 AC: 2AN: 246506Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133996
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.86e-7 AC: 1AN: 1458402Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 725286
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GnomAD4 genome AF: 0.0000203 AC: 3AN: 147694Hom.: 0 Cov.: 25 AF XY: 0.0000416 AC XY: 3AN XY: 72054
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | The HBA2 c.345delC; p.Ala116ProfsTer18 variant (rs746988006, HbVar ID: 3055) is reported heterozygous in the literature in multiple individuals affected with microcytosis and mild erythrocytosis (see HbVar and references therein, Eng 2006, Grimholt 2021). Further, this variant was observed in trans with the –SEA deletion in an individual with Hb Barts. This variant is reported in ClinVar (Variation ID: 439116) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the HBA2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein that would include a sequence of 18 amino acid residues not usually present. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Eng B et al. Three new alpha-thalassemia point mutations ascertained through newborn screening. Hemoglobin. 2006;30(2):149-53. PMID: 16798638. Grimholt RM et al. Hemoglobinopathy gone astray-three novel forms of a-thalassemia in Norwegian patients characterized by quantitative real-time PCR and DNA sequencing. Scand J Clin Lab Invest. 2021 Dec;81(8):670-678. PMID: 34791962. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 30, 2021 | The frameshift variant causes the premature termination of HBA2 protein synthesis, and is associated with alpha thalassemia and has been identified in a newborn who also carried the -alpha3.7 deletion variant (PMID: 16798638 (2006), PMID: 20507641 (2010) and PMID: 24672827 (2013)). Therefore, the variant is classified as pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at