GeneBe

rs28928882

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000517.6(HBA2):​c.219C>A​(p.His73Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000771 in 1,297,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H73D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)
Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

6
5
6

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: -0.0620

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 16 uncertain in NM_000517.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBA2NM_000517.6 linkc.219C>A p.His73Gln missense_variant Exon 2 of 3 ENST00000251595.11 NP_000508.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBA2ENST00000251595.11 linkc.219C>A p.His73Gln missense_variant Exon 2 of 3 1 NM_000517.6 ENSP00000251595.6

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
AF:
7.71e-7
AC:
1
AN:
1297758
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
645236
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
25250
American (AMR)
AF:
0.00
AC:
0
AN:
36944
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24492
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36002
South Asian (SAS)
AF:
0.00
AC:
0
AN:
76664
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
34956
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
3814
European-Non Finnish (NFE)
AF:
9.95e-7
AC:
1
AN:
1005220
Other (OTH)
AF:
0.00
AC:
0
AN:
54416
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
22

ClinVar

Significance: other
Submissions summary: Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

HEMOGLOBIN GOUDA Other:1
Jul 20, 2016
OMIM
Significance:other
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.35
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.16
CADD
Benign
16
DANN
Benign
0.95
DEOGEN2
Benign
0.029
.;T
Eigen
Benign
-0.12
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.084
N
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.48
D
PhyloP100
-0.062
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-5.5
D;D
REVEL
Uncertain
0.58
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.012
D;D
Vest4
0.56
MutPred
0.84
Loss of disorder (P = 0.1906);.;
MVP
1.0
MPC
2.0
ClinPred
0.99
D
GERP RS
2.2
PromoterAI
0.17
Neutral
gMVP
0.84

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: rs28928882; hg19: chr16-223247; API