rs281864885

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP3BP6

The NM_000517.6(HBA2):​c.337C>A​(p.His113Asn) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. H113Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 25)

Consequence

HBA2
NM_000517.6 missense

Scores

4
4
8

Clinical Significance

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

Conservation

PhyloP100: 0.150

Publications

0 publications found
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]
HBA2 Gene-Disease associations (from GenCC):
  • alpha thalassemia spectrum
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
  • erythrocytosis, familial, 7
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • hemoglobin M disease
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Hb Bart's hydrops fetalis
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin H disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • Heinz body anemia
    Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
  • methemoglobinemia, alpha type
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000517.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.804
BP6
Variant 16-173508-C-A is Benign according to our data. Variant chr16-173508-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3572112.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000517.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
HBA2
NM_000517.6
MANE Select
c.337C>Ap.His113Asn
missense
Exon 3 of 3NP_000508.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
HBA2
ENST00000251595.11
TSL:1 MANE Select
c.337C>Ap.His113Asn
missense
Exon 3 of 3ENSP00000251595.6
HBA2
ENST00000482565.1
TSL:1
n.473C>A
non_coding_transcript_exon
Exon 2 of 2
HBA2
ENST00000397806.1
TSL:2
c.241C>Ap.His81Asn
missense
Exon 3 of 3ENSP00000380908.1

Frequencies

GnomAD3 genomes
Cov.:
25
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
25

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
1
1
not provided (2)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.030
CADD
Benign
18
DANN
Benign
0.86
DEOGEN2
Benign
0.13
T
Eigen
Benign
-0.72
Eigen_PC
Benign
-0.80
FATHMM_MKL
Benign
0.15
N
M_CAP
Pathogenic
0.47
D
MetaRNN
Pathogenic
0.80
D
MetaSVM
Uncertain
0.065
D
PhyloP100
0.15
PrimateAI
Benign
0.46
T
PROVEAN
Pathogenic
-6.1
D
REVEL
Uncertain
0.45
Sift
Pathogenic
0.0
D
Sift4G
Benign
0.078
T
Vest4
0.29
MutPred
0.82
Loss of helix (P = 0.1299)
MVP
0.99
MPC
1.4
ClinPred
0.67
D
GERP RS
2.1
gMVP
0.81

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

Other links and lift over

dbSNP: rs281864885; hg19: chr16-223507; API