rs281865555
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_StrongBP6
The NM_000517.6(HBA2):āc.49A>Gā(p.Lys17Glu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. 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. K17M) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 2)
Exomes š: 0.000013 ( 0 hom. )
Consequence
HBA2
NM_000517.6 missense
NM_000517.6 missense
Scores
6
5
4
Clinical Significance
Conservation
PhyloP100: 4.35
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 Uncertain_significance. Variant got 3 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
BP6
Variant 16-172961-A-G is Benign according to our data. Variant chr16-172961-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15635.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | c.49A>G | p.Lys17Glu | missense_variant | 1/3 | ENST00000251595.11 | NP_000508.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.49A>G | p.Lys17Glu | missense_variant | 1/3 | 1 | NM_000517.6 | ENSP00000251595.6 | ||
HBA2 | ENST00000484216.1 | c.16A>G | p.Lys6Glu | missense_variant | 1/2 | 1 | ENSP00000495899.1 | |||
HBA2 | ENST00000482565.1 | n.68A>G | non_coding_transcript_exon_variant | 1/2 | 1 | |||||
HBA2 | ENST00000397806.1 | c.-2+3A>G | splice_region_variant, intron_variant | 2 | ENSP00000380908.1 |
Frequencies
GnomAD3 genomes Cov.: 2
GnomAD3 genomes
Cov.:
2
GnomAD4 exome AF: 0.0000130 AC: 5AN: 384714Hom.: 0 Cov.: 0 AF XY: 0.00000988 AC XY: 2AN XY: 202358
GnomAD4 exome
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5
AN:
384714
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2
AN XY:
202358
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GnomAD4 genome Cov.: 2
GnomAD4 genome
Cov.:
2
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1Other:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 21, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 17, 2023 | The HBA2 c.49A>G (p.Lys17Glu or Lys16Glu) variant, also known as Hb I, is reported as having normal function and stability. Individuals heterozygous for this variant have normal clinical presentations with Hb I being 15-28% of the total hemoglobin (PMID: 7803274 (1994), 6085353 (1984)). Based on the available information, we are unable to determine the clinical significance of this variant. - |
HEMOGLOBIN I (TEXAS) Other:1
other, no assertion criteria provided | literature only | OMIM | Mar 28, 2013 | - - |
HEMOGLOBIN I (SKAMANIA) Other:1
other, no assertion criteria provided | literature only | OMIM | Mar 28, 2013 | - - |
HEMOGLOBIN I (BURLINGTON) Other:1
other, no assertion criteria provided | literature only | OMIM | Mar 28, 2013 | - - |
HEMOGLOBIN I Other:1
other, no assertion criteria provided | literature only | OMIM | Mar 28, 2013 | - - |
HEMOGLOBIN I (PHILADELPHIA) Other:1
other, no assertion criteria provided | literature only | OMIM | Mar 28, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Uncertain
D
Vest4
MutPred
Loss of MoRF binding (P = 0.0034);
MVP
MPC
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at