rs1277780626
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The 16-172854-C-T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 0)
Exomes 𝑓: 0.0026 ( 12 hom. )
Failed GnomAD Quality Control
Consequence
HBA2
NM_000517.6 upstream_gene
NM_000517.6 upstream_gene
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.459
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 Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BS1
?
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00261 (332/127138) while in subpopulation AMR AF= 0.0325 (230/7070). AF 95% confidence interval is 0.0291. There are 12 homozygotes in gnomad4_exome. There are 144 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High Homozygotes in GnomAdExome4 at 12 AD,AR,Digenic gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | upstream_gene_variant | ENST00000251595.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | upstream_gene_variant | 1 | NM_000517.6 | P1 | ||||
HBA2 | ENST00000482565.1 | upstream_gene_variant | 1 | ||||||
HBA2 | ENST00000397806.1 | upstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 0Hom.: 0 Cov.: 0 FAILED QC
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GnomAD4 exome AF: 0.00261 AC: 332AN: 127138Hom.: 12 Cov.: 0 AF XY: 0.00215 AC XY: 144AN XY: 67122
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GnomAD4 genome ? Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 0Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 0
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?
Data not reliable, filtered out with message: AC0;AS_VQSR
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 28, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 13, 2023 | The c.-59C>T variant is a C>T change in the TATA box element of the promoter of the alpha2-globin gene. In an in vitro functional study, the c.-59C>T variant was found to cause an approximately 50% reduction in the level of transcription of the alpha2-globin gene (PMID: 24300714 (2014)). Individuals who are heterozygous for this variant are reported as having a normal clinical presentation (PMID: 24300714 (2014)). Based on the available information, we are unable to determine the clinical significance of this variant. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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