rs33999427

Positions:

• chr11-5225600-A-AGT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_000518.5(HBB):​c.441_442insAC​(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:3 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 150 codons.
• 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: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.441_442insAC	p.Ter148ThrfsTer12	frameshift_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.441_442insAC	p.Ter148ThrfsTer12	frameshift_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.441_442insAC	p.Ter148ThrfsTer12	frameshift_variant	3/3			P1
HBB	ENST00000633227.1	c.*257_*258insAC		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 13, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 13, 2017	- -

Hemoglobinopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Apr 01, 2021

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

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

-

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

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

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;