11-5227100-T-C

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 premature start codon gain 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_premature_start_codon_gain

Scores

2

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]

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 rank MANE Protein UniProt
HBBNM_000518.5 linkc.-79A>G upstream_gene_variant ENST00000335295.4 NP_000509.1 P68871D9YZU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBBENST00000335295.4 linkc.-79A>G upstream_gene_variant 1 NM_000518.5 ENSP00000333994.3 P68871

Frequencies

GnomAD3 genomes
AF:
0.000821
AC:
125
AN:
152186
Hom.:
0
Cov.:
33
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:
49
AN:
858236
Hom.:
0
Cov.:
12
AF XY:
0.0000378
AC XY:
17
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.:
0
Cov.:
33
AF XY:
0.000859
AC XY:
64
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.:
0
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
Sep 11, 2020
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 18, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Oct 14, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Nov 06, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The HBB c.-79A>G variant (also known as -29A>G) has been reported in published literature in affected individuals with beta(+)-thalassemia (PMIDs: 28385923 (2017), 26079343 (2015), 18294253 (2008), 9401495 (1997), 2458145 (1988)). The frequency of this variant in the general population, 0.0032 (28/8704 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. Genetic counseling and testing of at-risk relatives are recommended. -

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 (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
Mar 17, 2017
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Apr 26, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Nov 25, 2019
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

- -

Oct 18, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Inborn genetic diseases Pathogenic:1
Sep 23, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.-79A>G alteration is located in the 5' untranslated region (5'UTR) of the HBB gene. This alteration consists of a A to G substitution 79 nucleotides upstream from the first translated codon. Based on data from gnomAD, the G allele has an overall frequency of 0.089% (28/31390) total alleles studied. The highest observed frequency was 0.322% (28/8704) of African alleles. This variant, also known as -29A>G, has been identified in the homozygous state and/or in conjunction with other HBB variants in individuals with mild or major beta-thalassemia (Antonarakis, 1984; Gonzalez-Redondo, 1988; Ropero, 2017). This variant 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, 2013). Multiple functional studies show this variant leads to a reduction of mRNA (Antonarakis, 1984; Calvo, 2009). Based on the available evidence, this alteration is classified as pathogenic. -

Heinz body anemia Pathogenic:1
May 04, 2022
Mendelics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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 30, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Beta-plus-thalassemia Pathogenic:1
Oct 01, 1986
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
-0.18
CADD
Benign
20
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.

Other links and lift over

dbSNP: rs34598529; hg19: chr11-5248330; API