rs33999427

Variant names:

• chr11-5225600-A-AGT
• rs33999427
• NM_000518.5:c.440_441dupAC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000518.5(HBB):​c.440_441dupAC​(p.Ter148ThrfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 3.31

Genes affected

HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

ENSG00000285498 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00676 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5225600-A-AGT is Pathogenic according to our data. Variant chr11-5225600-A-AGT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 439161.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.440_441dupAC	p.Ter148ThrfsTer12	frameshift_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.440_441dupAC	p.Ter148ThrfsTer12	frameshift_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Sep 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the HBB gene (p.*148Thrext*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the natural stop codon of the HBB protein and extend the protein by 11 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with mild polycythemia, secondary erythrocytosis (PMID: 604313, 9494047, 12621249, 15768557, 20353353). This variant is also known as Hb Tak, HBB:c.441_442insAC. ClinVar contains an entry for this variant (Variation ID: 439161). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jun 13, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.440_441dup; p.Ter148ThrextTer11 variant (Hb Tak, also known as His147ext when numbered from the mature protein, rs33999427, HbVar ID:710) is reported in the literature as a common variant in the southeast Asian population with high oxygen affinity, typically associated with secondary erythrocytosis in the homozygous state or when compound heterozygous with Hb E (Hoyer 1998, Tanphaichitr 2003, Teawtrakul 2010). However, Hb Tak in combination with other globin variants such as Hb Constant Spring may result in severe hemolytic anemia (Choed-Amphai 2021, Panyasai 2016). Heterozygous carriers are typically asymptomatic, but may display mild microcytic anemia (Fucharoen 2012, Panyasai 2015, Shih 2005, Tanphaichitr 2003). This variant is also reported in ClinVar (Variation ID: 439161), but is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant inserts two nucleotides in the last codon of the gene, which is expected to disrupt the canonical termination codon and include eleven additional amino acid residues not usually present. Based on available information, this variant is considered to be likely pathogenic. References Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Choed-Amphai C et al. Coinherited Hemoglobin H/Constant Spring Disease and Heterozygous Hemoglobin Tak Causing Severe Hemolytic Anemia in a Thai Boy. J Pediatr Hematol Oncol. 2021 Jul 1;43(5):e723-e726. PMID: 32925409. Fucharoen S et al. Hb H disease with various beta hemoglobinopathies: molecular, hematological and diagnostic aspects. Hemoglobin. 2012;36(1):18-24. PMID: 22145566. Hoyer JD et al. Hb Tak confirmed by DNA analysis: not expressed as thalassemia in a Hb Tak/Hb E compound heterozygote. Hemoglobin. 1998 Jan;22(1):45-52. PMID: 9494047. Panyasai S et al. Hemoglobin Variants in Northern Thailand: Prevalence, Heterogeneity and Molecular Characteristics. Genet Test Mol Biomarkers. 2016 Jan;20(1):37-43. PMID: 26544676. Shih MC et al. Hb Tak: a beta chain elongation at the end of the beta chain, in a Taiwanese. Hemoglobin. 2005;29(1):65-7. PMID: 15768557. Tanphaichitr VS et al. Homozygous hemoglobin Tak causes symptomatic secondary polycythemia in a Thai boy. J Pediatr Hematol Oncol. 2003 Mar;25(3):261-5. PMID: 12621249. Teawtrakul N et al. Compound heterozygous Hb Tak/Hb E causes secondary erythrocytosis in a Thai family. Hemoglobin. 2010 Jan;34(2):165-8. PMID: 20353353. -

Hemoglobinopathy Pathogenic:1

Apr 01, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.440_441dupAC (p.X148ThrfsX12, also known as Hb Tak in the literature) causes a frameshift which results in an extension of the protein. The variant was absent in 251368 control chromosomes. c.440_441dupAC has been reported in the literature in homozygosity or compound heterozygosity with other pathogenic variants in individuals affected with Hemoglobinopathies, including polycythemia (e.g. Hoyer_1998, Tanphaichitr_2003). In some individuals, abnormal hemoglobin was detected by HPLC, however clinical symptoms were either mild or not reported (e.g.Flatz_1971, Jindadamrongwech_2010). The variant was also identified in an individual diagnosed with erythrocytosis whom was reported to carry this variant in compound heterozygosity with HbE, however, the proband's father with the identical genotype was not reported to have any clinical symptoms of disease, suggesting reduced penetrance (e.g. Teawtrakul_2010). Hb Tak has also recently been reported in a patient who also carried Hb Constant Spring (HbCS) and was affected with a severe form of hemolytic anemia (Choed-Amphai_2020). Several publications report experimental evidence indicating that cells with the variant have increased affinity for oxygen (e.g. Imai_2001, Tanphaichitr_2003). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Beta-thalassemia HBB/LCRB Pathogenic:1

-

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is predicted to result in a loss or disruption of normal protein function through altering the stop codon, which leads to elongate the protein length. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000439161 / PMID: 9494047). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

HEMOGLOBIN TAK Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs33999427; hg19: chr11-5246830;