GeneBe

16-177320-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000558.5(HBA1):​c.338A>G​(p.His113Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,942 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. H113D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HBA1
NM_000558.5 missense

Scores

6
2
8

Clinical Significance

other no assertion criteria provided O:2

Conservation

PhyloP100: 2.49

Publications

1 publications found
Variant links:
Genes affected
HBA1 (HGNC:4823): (hemoglobin subunit alpha 1) 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]
HBA1 Gene-Disease associations (from GenCC):
  • alpha thalassemia spectrum
    Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • erythrocytosis, familial, 7
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • 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
  • methemoglobinemia, alpha type
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • Heinz body anemia
    Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 12 uncertain in NM_000558.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBA1NM_000558.5 linkc.338A>G p.His113Arg missense_variant Exon 3 of 3 ENST00000320868.9 NP_000549.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBA1ENST00000320868.9 linkc.338A>G p.His113Arg missense_variant Exon 3 of 3 1 NM_000558.5 ENSP00000322421.5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459942
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726236
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33452
American (AMR)
AF:
0.00
AC:
0
AN:
44566
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26076
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39572
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86128
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52754
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111316
Other (OTH)
AF:
0.00
AC:
0
AN:
60310
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Significance: other
Submissions summary: Other:2
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

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

HEMOGLOBIN SERBIA 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
Benign
0.18
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Benign
19
DANN
Benign
0.95
DEOGEN2
Uncertain
0.64
D;.
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.48
LIST_S2
Benign
0.69
T;T
M_CAP
Pathogenic
0.60
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Benign
0.0
.;.
PhyloP100
2.5
PrimateAI
Benign
0.42
T
PROVEAN
Pathogenic
-6.6
D;D
Sift
Pathogenic
0.0
D;D
Sift4G
Benign
0.11
T;T
Vest4
0.19
ClinPred
0.98
D
GERP RS
3.4
Varity_R
0.84
gMVP
0.91
Mutation Taster
=41/59
disease causing

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: rs34713708; hg19: chr16-227319; API