rs33944208

chr11-5227159-G-Achr11-5227159-G-Cchr11-5227159-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_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

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]

HBB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000647020.1 linkuse as main transcript	c.-138C>T		5_prime_UTR_variant	1/3			P1
HBB	ENST00000380315.2 linkuse as main transcript	c.-18-120C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152178

Hom.:

Cov.:

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:

AN:

552662

Hom.:

Cov.:

AF XY:

0.0000635

AC XY:

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:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

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.:

Bravo

AF:

0.000314

Asia WGS

AF:

0.000289

AC:

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 submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	The 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 14, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 30, 2017	- -

beta Thalassemia

Pathogenic:2Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 23, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hemoglobinopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 08, 2018

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2017

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. -

Beta-plus-thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1984

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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