16-173253-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000517.6(HBA2):​c.224A>G​(p.Asp75Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D75A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Consequence

HBA2
NM_000517.6 missense

Scores

8
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.76
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_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HBA2NM_000517.6 linkc.224A>G p.Asp75Gly missense_variant 2/3 ENST00000251595.11 NP_000508.1 P69905D1MGQ2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HBA2ENST00000251595.11 linkc.224A>G p.Asp75Gly missense_variant 2/31 NM_000517.6 ENSP00000251595.6 P69905
HBA2ENST00000484216.1 linkc.191A>G p.Asp64Gly missense_variant 2/21 ENSP00000495899.1 A0A2R8Y7C0
HBA2ENST00000482565.1 linkn.360A>G non_coding_transcript_exon_variant 1/21
HBA2ENST00000397806.1 linkc.128A>G p.Asp43Gly missense_variant 2/32 ENSP00000380908.1 G3V1N2

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
24
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 06, 2024The HBA2 c.224A>G; p.Asp75Gly variant (also known as Asp74Gly when numbered from the mature protein, rs281864856) is reported in a pregnant individual with mild anemia, however, it was also found in her unaffected identical twin and father (Tang 2023). Another variant at this codon in the homologous HBA1 gene (Hb Chapel Hill, HBA1: c.224A>G; p.Asp75Gly, HbVar ID: 110) has been reported in the literature as an unstable variant with slightly increased oxygen affinity, and has been found in the heterozygous state in individuals with both mild, persistent erythrocytosis and mild anemia (see link to HbVar and references therein). The HBA2 c.224A>G; p.Asp75Gly variant is reported in ClinVar (Variation ID: 811237) but is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.848). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Tang B et al. Hb Chapel Hill or Alpha2 74(EF3) Asp>Gly, a mildly unstable variant found in a Chinese family. Hematology. 2023 Dec;28(1):2187154. PMID: 36939273. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.11
.;T
Eigen
Uncertain
0.38
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
0.99
D
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-6.0
D;D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0070
D;D
Vest4
0.74
MutPred
0.96
Loss of disorder (P = 0.1328);.;
MVP
1.0
MPC
2.7
ClinPred
1.0
D
GERP RS
4.2
gMVP
0.93

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: rs281864856; hg19: chr16-223252; API