rs281860607

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2PP3_StrongBP6

The NM_000517.6(HBA2):​c.237C>A​(p.Asn79Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N79H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 7.4e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 missense

Scores

1
4
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -7.80
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978
BP6
Variant 16-173266-C-A is Benign according to our data. Variant chr16-173266-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 618159.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBA2NM_000517.6 linkuse as main transcriptc.237C>A p.Asn79Lys missense_variant 2/3 ENST00000251595.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBA2ENST00000251595.11 linkuse as main transcriptc.237C>A p.Asn79Lys missense_variant 2/31 NM_000517.6 P1
HBA2ENST00000484216.1 linkuse as main transcriptc.207C>A p.Asn69Lys missense_variant 2/21
HBA2ENST00000482565.1 linkuse as main transcriptn.373C>A non_coding_transcript_exon_variant 1/21
HBA2ENST00000397806.1 linkuse as main transcriptc.141C>A p.Asn47Lys missense_variant 2/32

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
7.39e-7
AC:
1
AN:
1352784
Hom.:
0
Cov.:
25
AF XY:
0.00000149
AC XY:
1
AN XY:
671368
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.51e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 10, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoOct 18, 2021The HBA2 c.237C>A (p.Asn79Lys) variant is reported in the published literature in individuals with hemoglobin abnormalities (PMID: 32597250 (2020)) and anemia (21470372 (2011), 22625430 (2012), 25109349 (2014), 33823095 (2021)). In the individuals with anemia, this variant occurred with the HB Constant Spring and alpha 3.7 deletion variants in HBA2 (PMIDs: 21093326 (2011), 22625430 (2012), 33823095 (2021)). It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.032
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
0.11
DANN
Benign
0.91
DEOGEN2
Benign
0.010
.;T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.080
N
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Benign
-0.59
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-1.2
N;N
REVEL
Uncertain
0.41
Sift
Uncertain
0.0090
D;D
Sift4G
Benign
0.10
T;T
Vest4
0.69
MutPred
0.94
Gain of ubiquitination at N79 (P = 0.0162);.;
MVP
0.98
MPC
1.5
ClinPred
0.11
T
GERP RS
-4.5
gMVP
0.78

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: rs281860607; hg19: chr16-223265; API