rs281864889
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_000517.6(HBA2):c.389T>C(p.Leu130Pro) 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 26)
Consequence
HBA2
NM_000517.6 missense
NM_000517.6 missense
Scores
9
3
4
Clinical Significance
Conservation
PhyloP100: 7.17
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000517.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 16-173560-T-C is Pathogenic according to our data. Variant chr16-173560-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2691625.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | c.389T>C | p.Leu130Pro | missense_variant | 3/3 | ENST00000251595.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.389T>C | p.Leu130Pro | missense_variant | 3/3 | 1 | NM_000517.6 | P1 | |
HBA2 | ENST00000482565.1 | n.525T>C | non_coding_transcript_exon_variant | 2/2 | 1 | ||||
ENST00000702607.1 | n.101A>G | non_coding_transcript_exon_variant | 1/1 | ||||||
HBA2 | ENST00000397806.1 | c.293T>C | p.Leu98Pro | missense_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes Cov.: 26
GnomAD3 genomes
Cov.:
26
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 26
GnomAD4 genome
Cov.:
26
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
alpha Thalassemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 12, 2023 | Variant summary: HBA2 c.389T>C (p.Leu130Pro), also known as Hb Utrecht, results in a non-conservative amino acid change located in the Globin (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248988 control chromosomes. c.389T>C has been reported in the literature in multiple individuals from a large family affected with Alpha Thalassemia (example, Harteveld_1996). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absence of HBA protein by SDS-PAGE in RBC cells (Wajcman_2011). The following publications have been ascertained in the context of this evaluation (PMID: 8790146, 21950764). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Vest4
MutPred
Gain of disorder (P = 0.0138);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at