rs281864813

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4BP6_Moderate

The NM_000517.6(HBA2):​c.59C>A​(p.Ala20Glu) variant causes a missense 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 Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: not found (cov: 2)

Consequence

HBA2
NM_000517.6 missense

Scores

5
10

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.551
Variant links:
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 Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.30824098).
BP6
Variant 16-172971-C-A is Benign according to our data. Variant chr16-172971-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3767078.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBA2NM_000517.6 linkc.59C>A p.Ala20Glu missense_variant Exon 1 of 3 ENST00000251595.11 NP_000508.1 P69905D1MGQ2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBA2ENST00000251595.11 linkc.59C>A p.Ala20Glu missense_variant Exon 1 of 3 1 NM_000517.6 ENSP00000251595.6 P69905
HBA2ENST00000484216.1 linkc.26C>A p.Ala9Glu missense_variant Exon 1 of 2 1 ENSP00000495899.1 A0A2R8Y7C0
HBA2ENST00000482565.1 linkn.78C>A non_coding_transcript_exon_variant Exon 1 of 2 1
HBA2ENST00000397806.1 linkc.-2+13C>A intron_variant Intron 1 of 2 2 ENSP00000380908.1 G3V1N2

Frequencies

GnomAD3 genomes
Cov.:
2
GnomAD4 exome
Cov.:
0
GnomAD4 genome
Cov.:
2

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Nov 20, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The Hb J-Tashikuergan variant (HBA2: c.59C>A; p.Ala20Glu, also known as Asp19Glu when numbered from the mature protein, rs281864813, HbVar ID: 25) is reported in the literature in individuals with normal hematology (Xu 2021, HbVar database and references therein). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.52), but functional studies suggest it has normal stability, although it may interfere with measurement of HbA1c (Xu 2021, HbVar database and references therein). Based on available information, this variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Xu J et al. Unexpected HbA1c results in the presence of three rare hemoglobin variants. Scand J Clin Lab Invest. 2021 Feb;81(1):59-64. PMID: 33315479. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.051
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
3.0
DANN
Benign
0.85
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.055
N
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.31
T
MetaSVM
Benign
-0.37
T
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-1.0
N
REVEL
Uncertain
0.52
Sift
Uncertain
0.025
D
Sift4G
Benign
0.26
T
Vest4
0.20
MutPred
0.18
Gain of solvent accessibility (P = 0.0246);
MVP
0.98
MPC
1.5
ClinPred
0.057
T
GERP RS
-0.70
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs281864813; hg19: chr16-222970; API