rs281864811
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5
The NM_000517.6(HBA2):c.46G>A(p.Gly16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G16C) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 2)
Exomes 𝑓: 0.000028 ( 0 hom. )
Consequence
HBA2
NM_000517.6 missense
NM_000517.6 missense
Scores
1
3
11
Clinical Significance
Conservation
PhyloP100: 0.396
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 2 ACMG points.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr16-172958-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1683493.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | c.46G>A | p.Gly16Ser | missense_variant | 1/3 | ENST00000251595.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.46G>A | p.Gly16Ser | missense_variant | 1/3 | 1 | NM_000517.6 | P1 | |
HBA2 | ENST00000484216.1 | c.16G>A | p.Gly6Ser | missense_variant | 1/2 | 1 | |||
HBA2 | ENST00000482565.1 | n.65G>A | non_coding_transcript_exon_variant | 1/2 | 1 | ||||
HBA2 | ENST00000397806.1 | c.-2G>A | splice_region_variant, 5_prime_UTR_variant | 1/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 2
GnomAD3 genomes
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Cov.:
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GnomAD3 exomes AF: 0.0000187 AC: 1AN: 53380Hom.: 0 AF XY: 0.0000372 AC XY: 1AN XY: 26900
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GnomAD4 exome AF: 0.0000283 AC: 11AN: 388200Hom.: 0 Cov.: 0 AF XY: 0.0000245 AC XY: 5AN XY: 204132
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GnomAD4 genome ? Cov.: 2
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 09, 2023 | Variant summary: HBA2 c.46G>A (p.Gly16Ser) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 53380 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.46G>A has been reported in the literature as a non-informative heterozygous genotype in a proband who had a clinical diagnosis of beta-thalassemia attributed to two different compound heterozygous HBB gene variants, namely IVS-II-654C>T and the Southeast Asian (SEA) typehereditary persistence of fetal hemoglobin (SEA-HPFH) variant (Wu_2017). It has also been reported as a non-informative genotype in settings of alpha-thalassemia carrier testing and as an incidental variant in settings of HbA1c measurements (example, Xu_2021, Wu_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28901454, 34309461, 31286593, 30809867). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationTaster
Benign
D;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Vest4
MutPred
Gain of glycosylation at G16 (P = 0.0403);
MVP
MPC
ClinPred
T
GERP RS
gMVP
Splicing
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Calibrated prediction
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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