rs11549407
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000518.5(HBB):c.118C>T(p.Gln40Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000157 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
HBB
NM_000518.5 stop_gained
NM_000518.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.64
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]
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ACMG classification
Classification made for transcript
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 248 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-5226774-G-A is Pathogenic according to our data. Variant chr11-5226774-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 15402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226774-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| HBB | NM_000518.5 | c.118C>T | p.Gln40Ter | stop_gained | 2/3 | ENST00000335295.4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HBB | ENST00000335295.4 | c.118C>T | p.Gln40Ter | stop_gained | 2/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000269 AC: 41AN: 152144Hom.: 0 Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:36Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
beta Thalassemia Pathogenic:13Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 10, 2019 | NM_000518.4(HBB):c.118C>T(Q40*) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy. Please note that Q40* is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 1734721 and 21417574. Classification of NM_000518.4(HBB):c.118C>T(Q40*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
| Pathogenic, no assertion criteria provided | curation | The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Nov 25, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Aug 25, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Feb 10, 2016 | Our laboratory reported dual molecular diagnoses in HBB (NM_000518.4, c.118C>T) and KANSL1 (NM_001193466.1, c.985_995del) in one individual with reported features of delayed motor milestones, delayed speech, intellectual disability, dysmorphic features, familial short stature, minor beta-thalassemia, eye anomalies (strabismus, nearsighted) and cafe au lait spot on right upper chest. Brain MRI showed asymmetric prominent ventricles, possible undermyelination and amygdalo/hippocampal dysgenesis. The same variant has been found in 4 additional individuals with beta thalassemia trait. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 17, 2022 | PVS1, PS3, PM3 - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 08, 2016 | Variant summary: The c.118C>T variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein, which is a commonly known diease mechanism in hemoglobinopathy. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.217dupA, c.230delC, c.251delG, etc. ). This variant is found in 51/121354 control chromosomes at a frequency of 0.0004203, which does not exceed maximal expected frequency of a pathogenic allele (0.0111803). This variant is a well-known common pathogenic variant in Sardinian and other populations (Danjou_2012, Sirdah_2013). Multiple reputable databases classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 20, 2024 | The p.Gln40X variant, also reported as p.Gln39X, in HBB is a well-known pathogenic variant that has been identified in the homozygous or compound heterozygous state with another pathogenic variant in >300 individuals with beta thalassemia (Rosatelli 1992 PMID: 1734721, Ghedira 2011 PMID: 21417574, Danjou 2012 PMID: 22271886, Sirdah 2013 PMID: 23321370, Herrera 2015 PMID: 25572186, Gallagher 2016 PMID: 27821015, Hussain 2017 PMID: 28670940, Carrocini 2017 PMID: 28366028). It has also been reported by other clinical laboratories in ClinVar (Variation ID 15402). Additionally, it has been identified in 0.02% (14/60012) of Admixed American and 0.02% (80/12912216/11800180) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). However, this frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 40 and has shown decreased mRNA expression level with no protein detected in p.Arg40X transfected Hela cells, suggesting that the variant undergoes nonsense-mediated mRNA decay (Neu-Yilik 2011 PMID: 21389146). Biallelic loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PM2_Supporting. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 10, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 15, 2016 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Feb 11, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Apr 18, 2019 | This nonsense variant found in exon 2 of 3 is predicted to result in loss of normal protein function. This variant has been previously reported in trans with a second HBB variant in individuals affected with with beta-thalassemia (PMID: 6457059, 23637309, 21417574, 27821015, 20301599). The variant was been classified as Pathogenic by multiple clinical laboratories in the ClinVar database (Variation ID: 15402). Functional studies of the variant using transfected Hela cells demonstrate significantly reduced mRNA expression with no protein detected, suggesting that the variant transcript undergoes nonsense-mediated mRNA decay (PMID: 21389146). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (87/282760). Based on the available evidence the c.118C>T (p.Gln40Ter) variant is classified as Pathogenic. - |
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | HBB: PM3:Very Strong, PVS1, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Gln40*) 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 present in population databases (rs11549407, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with beta-thalassemia (PMID: 8095930, 25572186, 27427187, 28366028). This variant is also known as p.Gln39X. ClinVar contains an entry for this variant (Variation ID: 15402). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 26, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | The Codon 39 C>T variant (HBB c.118C>T; p.Gln40Ter, also known as Gln39Ter when numbered from the mature protein, rs11549407, HbVar ID: 845) induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. This variant is one of the most common Mediterranean beta(0) thalassemia variants (see HbVar link and references therein) and is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 21, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 01, 2020 | The HBB c.118C>T (p.Gln40*) variant causes the premature termination of beta-globin protein synthesis and is associated with beta-zero thalassemia (see HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter), and PMID: 6457059 (1981), 6985481 (1981), 6896219 (1982)). Previous names for this pathogenic variant include codon 39 (C>T) and Gln39X. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2022 | One of the major beta-thalassemia alleles in the Mediterranean area (HbVar ID 845; Giardine et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect with significantly reduced mRNA expression level in R40X transfected Hela cells with no protein detected, suggesting that the variant transcript undergoes nonsense-mediated mRNA decay (Neu-Yilik et al., 2011); Identified in multiple individuals with beta-thalassemia minor or beta-thalassemia trait referred for genetic testing at GeneDx; Q40X has also been reported as Q39X using alternative nomenclature; This variant is associated with the following publications: (PMID: 2867271, 21417574, 25087612, 22975760, 1734721, 25572186, 21228398, 20301599, 6457059, 27821015, 8095930, 28670940, 27959697, 28366028, 24137000, 30665703, 31784700, 27427187, 32248411, 8103502, 34426522, 8195005, 1795494, 33326653, 31589614, 15609277, 9629495, 33339817, 9163586, 2577233, 21389146) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 19, 2017 | - - |
Beta-thalassemia HBB/LCRB Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 24, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Feb 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 17, 2023 | _x000D_ Criteria applied: PVS1, PS3, PS4, PP4 - |
| Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 24, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 13, 2023 | ACMG classification criteria: PVS1 very strong, PS4 strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.031%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015402 / PMID: 6457059). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Hb SS disease Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 09, 2023 | The HBB c.118C>T (p.Gln40Ter) nonsense variant, also referred to as p.Gln39Ter, results in the loss of normal protein function through nonsense-mediated mRNA decay. This variant is one of the commonly identified pathogenic variants in individuals with beta-thalassemia from the Mediterranean region, accounting for most cases in Sardinia (PMID: 23637309). The p.Gln40Ter variant has been reported in a homozygous or compound heterozygous state in more than 300 individuals with different forms of beta-thalassemia (PMID: 9163586; 22271886; 23321370; 27199182; 33000750). The frequency of this allele in the Genome Aggregation Database is 0.000655 in the Latino/Admixed American population (version 3.1.2). A functional study using HeLa cells showed reduced mRNA expression with no protein detected in cells transfected with the variant compared to wildtype, suggesting the variant undergoes nonsense mediated mRNA decay (PMID: 21389146). Based on the available evidence, the c.118C>T (p.Gln40Ter) variant is classified as pathogenic for sickle cell disease. - |
Beta zero thalassemia Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1992 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 09, 2016 | The p.Q40* pathogenic mutation (also known as c.118C>T and p.Q39X), located in coding exon 2 of the HBB gene, results from a C to T substitution at nucleotide position 118. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This mutation was first reported in the Sardinian population and in an Italian individual with beta0-thalassemia (Trecartin RF et al. J. Clin. Invest., 1981 Oct;68:1012-7; Orkin SH et al. J. Biol. Chem., 1981 Oct;256:9782-4). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
alpha Thalassemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 28, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM1. - |
alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:Methemoglobinemia, beta-globin type;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 01, 2022 | - - |
Heinz body anemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Apr 10, 2022 | The c.118C>T;p.(Gln40*) variant creates a premature translational stop signal in the HBB gene. It is expected to result in an absent or disrupted protein product -PVS1.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 2867271)PS3. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 15402; PMID: 20301599; 27199182; 28361595; 27829304; 28670940; 28366028; 26897028; 32039214; 26366554; 6457059; 28366028) - PS4. The variant is present at low allele frequencies population databases (rs11549407 – gnomAD 0.002695%; ABraOM 0.000854 frequency - https://abraom.ib.usp.br/) - PM2_supporting. The p.(Gln40*) was detected in trans with a pathogenic variant (PMID: 28361595; 26956563) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Malaria, susceptibility to Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
HBB-related condition Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 24, 2023 | The HBB c.118C>T variant is predicted to result in premature protein termination (p.Gln40*). The c.118C>T change is a pathogenic founder variant in Sardina and is also referred to as codon 39C>T (Rosatelli MC et al 1992. PubMed ID: 1734721; Trecartin et al 1981. PubMed ID: 6457059; Sirdah et al. 2013. PubMed ID: 23321370). This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
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Pathogenic
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Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at