Variant rs34598529 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The ENST00000647020.1(HBB):c.-79A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,010,540 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

HBB
ENST00000647020.1 5_prime_UTR

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 2.39

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 11-5227100-T-C is Pathogenic according to our data. Variant chr11-5227100-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 15469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227100-T-C is described in Lovd as [Pathogenic]. Variant chr11-5227100-T-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.18).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5 linkuse as main transcript			upstream_gene_variant		ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript			upstream_gene_variant		1	NM_000518.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000821

AC:

125

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000571

AC:

AN:

858236

Hom.:

Cov.:

AF XY:

0.0000378

AC XY:

AN XY:

450228

show subpopulations

Gnomad4 AFR exome

AF:

0.00217

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000493

GnomAD4 genome

AF:

0.000827

AC:

126

AN:

152304

Hom.:

Cov.:

AF XY:

0.000859

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00301

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.00117

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 13, 2019	This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Found in at least one patient with expected phenotype for this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2022	Published functional studies demonstrate a damaging effect: reduced beta-globin RNA compared to wildtype (Antonarakis et al., 1984; Calvo et al., 2009); Also known as c.-29 A>G using alternate nomenclature; This variant is associated with the following publications: (PMID: 2458145, 30275481, 22975760, 19372376, 6583702, 2123063, 2014803, 8435318, 3021607, 8330981, 28366028, 28385923, 31395865, 31589614, 32746448) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	The HBB c.-79A>G variant (rs34598529, HbVar ID: 767), also known as -29 (A>G), is reported in the literature in multiple patients with beta (+) thalassemia, and has been found in a homozygous state or in-trans with another pathogenic HBB variant (Antonarakis 1984, Carrocini 2017, Huang 1986, Ropero 2017, HbVar database and references therein). Functional characterization of this variant indicates a significant reduction of beta globin transcription to 25 percent of normal levels (Antonarakis 1984). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 15469), and is found in the African population with an allele frequency of 0.32% (28/8,704 alleles) in the Genome Aggregation Database. The variant lies in the conserved proximal promoter of HBB, and is predicted to affect transcription factor binding. Based on available information, the c.-79A>G variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Antonarakis S et al. beta-Thalassemia in American Blacks: novel mutations in the "TATA" box and an acceptor splice site. Proc Natl Acad Sci U S A. 1984 81(4):1154-8. PMID: 6583702. Carrocini GCS et al. Mutational Profile of Homozygous B-Thalassemia in Rio de Janeiro, Brazil. Hemoglobin. 2017 Jan;41(1):12-15. PMID: 28366028. Huang S et al. The same "TATA" box beta-thalassemia mutation in Chinese and US blacks: another example of independent origins of mutation. Hum Genet. 1986 74(2):162-4. PMID: 3021607. Ropero P et al. Phenotype of mutations in the promoter region of the B-globin gene. J Clin Pathol. 2017 Oct;70(10):874-878. PMID: 28385923. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	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 (rs34598529, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with autosomal recessive beta thalassemia (PMID: 2123063, 2458145, 3021607, 6583702, 28385923). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-29A>G . Studies have shown that this variant alters HBB gene expression (PMID: 6583702). For these reasons, this variant has been classified as Pathogenic. -

beta Thalassemia

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000518.4(HBB):c.-79A>G(aka -29A>G) is classified as pathogenic and is associated with beta thalassemia. Sources cited for classification include the following: PMID: 2458145, and 6583702. Classification of NM_000518.4(HBB):c.-79A>G(aka -29A>G) is based on the following criteria: This is a well-established pathogenic variant in the literature that 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2016	Variant summary: The c.-79A>G variant affects a conserved nucleotide in TATA box in 5'UTR. One in-silico tool predicts damaging outcome for this variant. This variant is found in 2/5008 control chromosomes at a frequency of 0.0003994, which does not exceed maximal expected frequency of a pathogenic allele (0.0111803). In functional studies the variant of interest was shown to reduce the production of the b-globin mRNA. This change is a widely accepted to be deleterious and multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2016

The c.-79A>G pathogenic mutation (also known as -29A>G) is located in the 5' untranslated region (5’ UTR) of the HBB gene. This pathogenic mutation results from an A to G substitution 79 bases upstream from the first translated codon. In one study, this mutation was confirmed to be homozygous in an African American female with mild beta-thalassemia, whose mother was confirmed to be a heterozygous carrier. In addition, in vitro studies showed a mild reduction in beta-globin RNA transcripts (75% of wild-type) (Antonarakis SE et al. Proc. Natl. Acad. Sci. U.S.A. 1984;81(4):1154-8). In a luciferase reporter assay, a moderate reduction in mRNA was observed in addition to a significant decrease in protein levels (p <2e-12) in cells transfected with c.-79A>G (Calvo SE et al. Proc. Natl. Acad. Sci. U.S.A., 2009 May;106:7507-12). This mutation is one of the most common HBB mutations and has been observed in numerous Chinese and African American newborns with clinically significant beta-thalassemia ascertained through California's newborn screening program (Hoppe CC et al. Int J Lab Hematol 2013; 35(3):297-305). Based on the supporting evidence, c.-79A>G is interpreted as a disease-causing mutation. -

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

Apr 02, 2022

- -

Heinz body anemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Beta-plus-thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1986

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.18

Cadd

Benign

Dann

Benign

0.94

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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