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rs33944208

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The ENST00000647020.1(HBB):c.-138C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000823 in 704,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

HBB
ENST00000647020.1 5_prime_UTR

Scores

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 1.75
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP5
Variant 11-5227159-G-A is Pathogenic according to our data. Variant chr11-5227159-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227159-G-A is described in Lovd as [Pathogenic]. Variant chr11-5227159-G-A is described in Lovd as [Likely_pathogenic]. Variant chr11-5227159-G-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.41).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBBENST00000647020.1 linkuse as main transcriptc.-138C>T 5_prime_UTR_variant 1/3 P1
HBBENST00000380315.2 linkuse as main transcriptc.-18-120C>T intron_variant 5

Frequencies

GnomAD3 genomes
AF:
0.000204
AC:
31
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000603
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000956
GnomAD4 exome
AF:
0.0000489
AC:
27
AN:
552662
Hom.:
0
Cov.:
5
AF XY:
0.0000635
AC XY:
19
AN XY:
298996
show subpopulations
Gnomad4 AFR exome
AF:
0.000697
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000227
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000660
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
152296
Hom.:
0
Cov.:
33
AF XY:
0.000228
AC XY:
17
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.000601
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000151
Hom.:
0
Bravo
AF:
0.000314
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJun 30, 2017- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 23, 2022Occurs in a non-coding region of the gene, upstream of the ATG translation start codon; Published functional studies demonstrate that this variant results in a reduction of beta-globin mRNA compared to wild type beta-globin (Orkin et al., 1984); Also known as -88C>T; This variant is associated with the following publications: (PMID: 28385923, 16732578, 22975760, 27263053, 7909640, 26202972, 28366028, 28670940, 9163586, 32172616, 31395865, 6086605, 26372288) -
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 14, 2023This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs33944208, gnomAD 0.09%). This variant has been observed in individual(s) with autosomal recessive beta thalassemia (PMID: 2458145, 27263053, 28385923). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as -88C>T. ClinVar contains an entry for this variant (Variation ID: 15460). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects HBB function (PMID: 6086605). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 28, 2023The c.-138C>T variant (rs33944208, HbVar ID:756), also known as -88 C>T, has been reported in multiple patients with mild microcytic anemia (Orkin 1984, Wong 1986, Gonzalez-Redondo 1988), and has been found in-trans with other HBB pathogenic variants (Muniz 2000, Gonzalez-Redondo 1988, HbVar database). Functional characterization indicates that the variant alters the binding of transcription factors to the betaglobin promoter, and reduces the expression of HBB mRNA by 3 to 5 fold (Orkin 1984, HbVar database). This variant is found in the African population with an allele frequency of 0.09% (8/8708 alleles) in the Genome Aggregation Database. Based on the above information, the variant is classified as pathogenic. References: Link to HbVar database: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Gonzalez-Redondo JM et al. Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. Blood. 1988 Sep;72(3):1007-14. PMID: 2458145. Muniz A et al. Beta-thalassaemia in Cubans: novel allele increases the genetic diversity at the HBB locus in the Caribbean. Am J Hematol. 2000 May;64(1):7-14. PMID: 10815781. Orkin SH et al. Base substitution at position -88 in a beta-thalassemic globin gene. Further evidence for the role of distal promoter element ACACCC. J Biol Chem. 1984 Jul 25;259(14):8679-81. PMID: 6086605. Wong C et al. On the origin and spread of beta-thalassemia: recurrent observation of four mutations in different ethnic groups. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6529-32. PMID: 3462712. -
beta Thalassemia Pathogenic:2Other:1
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 20, 2019NM_000518.4(HBB):c.-138C>T(aka -88C>T) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-plus variant. Sources cited for classification include the following: PMID 2458145 and 6086605. Classification of NM_000518.4(HBB):c.-138C>T(aka -88C>T) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
not provided, no classification providedliterature onlyGeneReviews-- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.May 23, 2017- -
Hemoglobinopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 08, 2018Variant summary: HBB c.-138C>T involves the alteration of a conserved nucleotide that is located in the untranscribed region upstream of the HBB gene region, in the promoter region. The variant allele was found at a frequency of 0.00026 in 30972 control chromosomes, predominantly observed within the African subpopulation at a frequency of 0.00092 in the gnomAD database. c.-138C>T has been reported in the literature in multiple individuals of African origin who were affected with Beta Thalassemia Intermedia and mixed heterozygous hemoglobinopathies (e.g. Orkin 1984, Beris 1992, Muniz 2000, Carrocini 2017, Silva 2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on mRNA expression, and demonstrated about a 3-5 times lower expression of the variant mRNA compared with the wild type (Orkin 1984). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic (1x)/likely pathogenic(1x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 21, 2017The c.-138C>T pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the HBB gene. This pathogenic mutation results from a C to T substitution 138 bases upstream from the first translated codon. In one study, this mutation was detected in the homozygous state in 3 individuals with mild beta-thalassemia and in 2 individuals in conjunction with hemoglobin S (Gonzalez-Redondo JM et al. Blood, 1988 Sep;72:1007-14). In addition, in vitro studies showed a 3-5 times reduction in beta-globin RNA transcripts compared to wild type (Orkin SH et al. J. Biol. Chem., 1984 Jul;259:8679-81). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Beta-plus-thalassemia Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 1984- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.41
Cadd
Benign
19
Dann
Benign
0.66

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs33944208; hg19: chr11-5248389; API