rs193922555

Positions:

• chr11-5226640-GC-G

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.251del​(p.Gly84AlafsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HBB NM_000518.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -0.401

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 is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 75 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5226640-GC-G is Pathogenic according to our data. Variant chr11-5226640-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 36306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226640-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.251del	p.Gly84AlafsTer6	frameshift_variant	2/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.251del	p.Gly84AlafsTer6	frameshift_variant	2/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 24, 2017	Variant summary: The HBB c.251delG (p.Gly84Alafs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.287dupA, p.Leu97fs). The variant of interest has not been found in a large and broad control population from ExAC in 121390 control chromosomes. This variant was reported in patients with beta thalassemia in a homozygous state as well compound heterozygotes with other pathogenic variants, including evidence of cosegregation with disease (El-Kalla_1997, Rahimi_2010, Al-Allawi_2014, and Ulasli_2015). In an Iraqi study that included 74 beta thalassemia patients, it was found in nine patients and was the third most common mutation (Al-Allawi_2014). In another Iranian study that included 185 beta thalassemia patients, its allele frequency was 1.08% (Rahimi_2010). Available data including clinical and biochemical picture of heterozygous carriers supports that this variant causes transfusion-dependent thalassemia in a homozygous state or in a compound heterozygous state with another severe (beta0) variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 16, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 12, 2022	The HBB c.251del (p.Gly84Alafs*6) variant (also known as 250delG and 82/83 (-G)) alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant is associated with beta(0)-thalassemia (PMIDs: 28670940 (2017), 24719849 (2014), 1740317 (1992),1517107 (1992), 2525253 (1989)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 06, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change creates a premature translational stop signal (p.Gly84Alafs*6) 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 beta thalassemia (PMID: 2525253, 24719849, 27756326, 28670940). This variant is also known as 250delG and 82/83 (-G). ClinVar contains an entry for this variant (Variation ID: 36306). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 09, 2023	The HBB c.251delG; p.Gly84AlafsTer6variant (also known as Codons 82/83 (-G), rs193922555, HbVar ID: 875) is reported in the literature in multiple individuals with beta(0) thalassemia in the homozygous or compound heterozygous state (see HbVar and references therein, Al-Allawi 2014, Hancer 2020, Ulasli 2015). This variant is also reported in ClinVar (Variation ID: 36306), but is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, 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 Al-Allawi NA et al. Beta-thalassemia intermedia in Northern Iraq: a single center experience. Biomed Res Int. 2014;2014:262853. PMID: 24719849. Hançer VS et al. Two Rare Pathogenic HBB Variants in a Patient with Beta-Thalassemia Intermedia. Turk J Haematol. 2020 May 6;37(2):135-136. PMID: 32069775. Ulasli M et al. Novel ?eta-Thalassemia Mutation in Turkish Children. Indian J Hematol Blood Transfus. 2015 Jun;31(2):218-22. PMID: 25825561. -

Beta-thalassemia HBB/LCRB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Jun 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922555; hg19: chr11-5247870;