rs281864898

Variant names:

• chr11-5226947-ACCAACTT-A
• rs281864898
• NM_000518.5:c.68_74delAAGTTGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000518.5(HBB):​c.68_74delAAGTTGG​(p.Glu23ValfsTer37) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.15

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 339 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5226947-ACCAACTT-A is Pathogenic according to our data. Variant chr11-5226947-ACCAACTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 869360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226947-ACCAACTT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.68_74delAAGTTGG	p.Glu23ValfsTer37	frameshift_variant	Exon 1 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.68_74delAAGTTGG	p.Glu23ValfsTer37	frameshift_variant	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu23Valfs*37) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive beta-thalassemia (PMID: 21232998). ClinVar contains an entry for this variant (Variation ID: 869360). For these reasons, this variant has been classified as Pathogenic. -

Jun 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.68_74del; p.Glu23ValfsTer37 variant (also known as Codons 22/23/24 (-AAGTTGG) or as Glu22fs when numbered from the mature protein, rs281864898, ClinVar ID: 869360, HbVar ID: 803) is a beta(0) allele reported in the literature in several compound heterozygous individuals affected with beta thalassemia (Nadkarni 2009, Polat 2016, Tagiev 1993, HbVar database and references therein). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting seven nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Nadkarni A et al. Hematological and molecular analysis of novel and rare beta-thalassemia mutations in the Indian population. Hemoglobin. 2009;33(1):59-65. PMID: 19205975. Polat C et al. Codon 8 (-AA) and Codons 22/23/24 (-AAGTTGG) Compound Heterozygous Deletion Mutation in the Beta-Globin Gene: The First Report in Turkey. Open Access Lib J. 2016;3:1-4. Tagiev AF et al. The spectrum of beta-thalassemia mutations in Azerbaijan. Hum Mutat. 1993;2(2):152-4. PMID: 8318994. -

Jun 25, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.68_74del (p.Glu23Valfs*37) variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant has been reported in the published literature in multiple individuals affected with phenotypes ranging from a severe beta thalassemia to thalassemia intermedia (PMIDs: 8226099 (1993), 8318994 (1993), 21232998 (2011), 23637309 (2013), and 27453201 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

beta Thalassemia Pathogenic:2

Jan 17, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.68_74delAAGTTGG (p.Glu23ValfsX37) results in a premature termination codon and is predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251294 control chromosomes (gnomAD). c.68_74delAAGTTGG has been reported in the literature in individuals affected with Beta Thalassemia (e.g. Neishabury_2011). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 21232998). ClinVar contains an entry for this variant (Variation ID: 869360). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 25, 2019

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

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: rs281864898; hg19: chr11-5248177;