rs33944208

Variant names:

• chr11-5227159-G-A
• rs33944208
• ENST00000647020.1:c.-138C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-5227159-G-A
• chr11-5227159-G-C
• chr11-5227159-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 1.75

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.-138C>T		upstream_gene_variant		ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.-138C>T		upstream_gene_variant		1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152178 Hom.: 0 Cov.: 33

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

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

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:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB 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. -

Mar 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

Aug 23, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Occurs 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) -

Feb 06, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.-138C>T variant (also known as c.-50-88C>T and HBB -88C>T) has been reported in the published literature in affected individuals with beta thalassemia (PMIDs: 16732578 (2008), 27117567 (2016), 27263053 (2016), 27765567 (2017), 28385923 (2017), and 33947296 (2023)). Experimental studies have shown that this variant has an inconclusive effect on HBB function (PMIDs: 6086605 (1984) and 31395865 (2023)). 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 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 23, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_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. -

Hemoglobinopathy Pathogenic:1

Nov 08, 2018

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.-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

Apr 21, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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. -

Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1

May 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Beta-plus-thalassemia Pathogenic:1

Jul 01, 1984

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Other links and lift over

dbSNP: rs33944208; hg19: chr11-5248389;