NM_000558.5:c.263A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B.

Score: 10 - Pathogenic
10
-12 -7 -6 -1 0 5 6 9 10 12
PM1PM2PM5PP3_Strong

The NM_000558.5(HBA1):​c.263A>G​(p.His88Arg) variant causes a missense change. 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 other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H88N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

HBA1
NM_000558.5 missense

Scores

10
5
3

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 6.64

Publications

5 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)

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 uncertain in NM_000558.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-177095-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBA1NM_000558.5 linkc.263A>G p.His88Arg missense_variant Exon 2 of 3 ENST00000320868.9 NP_000549.1 P69905D1MGQ2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBA1ENST00000320868.9 linkc.263A>G p.His88Arg missense_variant Exon 2 of 3 1 NM_000558.5 ENSP00000322421.5 P69905

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

HEMOGLOBIN IWATA Other:1
May 10, 2018
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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.44
T;.
Eigen
Benign
0.11
Eigen_PC
Benign
0.092
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
PhyloP100
6.6
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-7.7
D;D
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0060
D;D
Vest4
0.88
MutPred
0.96
Loss of ubiquitination at K91 (P = 0.051);.;
MVP
1.0
ClinPred
1.0
D
GERP RS
3.2
PromoterAI
0.032
Neutral
Varity_R
0.97
gMVP
1.0

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: rs33976776; hg19: chr16-227095; API