11-5227100-T-C

Variant names:

• chr11-5227100-T-C
• rs34598529
• ENST00000647020.1:c.-79A>G

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.-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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 2.39

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 11-5227100-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
HBB	NM_000518.5	c.-79A>G		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.-79A>G		upstream_gene_variant		1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152186 Hom.: 0 Cov.: 33

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

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

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:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 06, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 11, 2020	- -
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 18, 2024	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	Labcorp Genetics (formerly Invitae), Labcorp	Mar 14, 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:4 Other:1

Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
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, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 30, 2024

- -

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	20
DANN	Benign	0.94

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34598529; hg19: chr11-5248330;