rs281864814

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000517.6(HBA2):​c.61C>G​(p.His21Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H21Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 2)

Consequence

HBA2
NM_000517.6 missense

Scores

5
3
7

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: -0.363
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 Uncertain_significance. Variant got 4 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBA2NM_000517.6 linkc.61C>G p.His21Asp 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.61C>G p.His21Asp missense_variant Exon 1 of 3 1 NM_000517.6 ENSP00000251595.6 P69905
HBA2ENST00000484216.1 linkc.28C>G p.His10Asp missense_variant Exon 1 of 2 1 ENSP00000495899.1 A0A2R8Y7C0
HBA2ENST00000482565.1 linkn.80C>G non_coding_transcript_exon_variant Exon 1 of 2 1
HBA2ENST00000397806.1 linkc.-2+15C>G 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: other
Submissions summary: Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

HEMOGLOBIN NIKAIA Other:1
Mar 28, 2013
OMIM
Significance: other
Review Status: no assertion criteria provided
Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Benign
13
DANN
Benign
0.70
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.14
N
M_CAP
Pathogenic
0.56
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Benign
-0.34
T
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-5.0
D
REVEL
Uncertain
0.52
Sift
Uncertain
0.0050
D
Sift4G
Benign
0.24
T
Vest4
0.76
MutPred
0.87
Loss of MoRF binding (P = 0.0658);
MVP
0.99
MPC
1.7
ClinPred
0.38
T
GERP RS
-1.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs281864814; hg19: chr16-222972; API