rs41464951
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong
The NM_000517.6(HBA2):c.427T>A(p.Ter143LysextTer31) variant causes a stop lost change. The variant allele was found at a frequency of 0.00000206 in 1,459,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 25)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
HBA2
NM_000517.6 stop_lost
NM_000517.6 stop_lost
Scores
3
1
3
Clinical Significance
Conservation
PhyloP100: 4.12
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Stoplost variant in NM_000517.6 Downstream stopcodon found after 154 codons.
PP5
?
Variant 16-173598-T-A is Pathogenic according to our data. Variant chr16-173598-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 15626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | c.427T>A | p.Ter143LysextTer31 | stop_lost | 3/3 | ENST00000251595.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.427T>A | p.Ter143LysextTer31 | stop_lost | 3/3 | 1 | NM_000517.6 | P1 | |
HBA2 | ENST00000482565.1 | n.563T>A | non_coding_transcript_exon_variant | 2/2 | 1 | ||||
ENST00000702607.1 | n.63A>T | non_coding_transcript_exon_variant | 1/1 | ||||||
HBA2 | ENST00000397806.1 | c.331T>A | p.Ter111LysextTer31 | stop_lost | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 25
GnomAD3 genomes
?
Cov.:
25
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1459094Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2AN XY: 725622
GnomAD4 exome
AF:
AC:
3
AN:
1459094
Hom.:
Cov.:
33
AF XY:
AC XY:
2
AN XY:
725622
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 25
GnomAD4 genome
?
Cov.:
25
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | This sequence change disrupts the translational stop signal of the HBA2 mRNA. It is expected to extend the length of the HBA2 protein by 31 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with hemoglobin H disease (PMID: 2372512, 8602995, 21637442). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Hb Icaria in literature. ClinVar contains an entry for this variant (Variation ID: 15626). This variant results in an extension of the HBA2 protein. Other variant(s) that result in a similarly extended protein product (p.*143Glnext*31) have been determined to be pathogenic (PMID: 2298455, 4944483, 12393486, 20507641). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 25, 2019 | The variant disrupts the natural stop codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. - |
beta Thalassemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The p.X143LysextX32 variant in HBA2 (also known as Hb-Icaria) has been reported in the compound heterozygous state (with a deletion) in at least 2 individuals with hemoglobin H disease and in carriers with haematological findings comparable to those with a deletional type of alpha-thalassaemia-2 (Efremov 1990 PMID: 2372512, Kanavakis 1996 PMID: 8602995, Kimura 2009 21637442). This variant has also been reported in ClinVar (Variation ID: 15626) and was absent from large population studies. This variant abolished the termination codon and results in an extension of the HBA2 protein. Additional variants that result in a similarly extended protein product have been reported in individuals with disease and have been classified as Pathogenic by multiple submitters in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hb H disease. ACMG/AMP Criteria applied: PM3 strong, PM2_supporting, PM4. - |
alpha Thalassemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jul 30, 2024 | The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Stop lost variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21637442, 2372512, 8602995). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 2372512). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015626 / PMID: 21637442, 2372512, 8602995). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Hemoglobin H disease, nondeletional Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1996 | - - |
HEMOGLOBIN ICARIA Other:1
other, no assertion criteria provided | literature only | OMIM | May 21, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
N;N
Vest4
GERP RS
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