11-5227099-T-G

Position:

• chr11-5227099-T-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.-78A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 865,286 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 1.34

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5227099-T-G is Pathogenic according to our data. Variant chr11-5227099-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 15470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227099-T-G is described in Lovd as [Pathogenic]. Variant chr11-5227099-T-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.5227099T>G		intergenic_region
HBB	NM_000518.5	c.-78A>C		upstream_gene_variant		ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.-78A>C		upstream_gene_variant		1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000347 AC: 3 AN: 865286 Hom.: 0 Cov.: 12 AF XY: 0.00000220 AC XY: 1 AN XY: 453722

Gnomad4 AFR exome AF: 0.00

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: 0.00000175

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 10, 2017	Variant summary: The HBB c.-78A>C variant involves the alteration of a non-conserved nucleotide in the promoter region (transcriptional TATA box). One in silico tool predicts a damaging outcome for this variant. The variant of interest was observed in controls with an allele frequency of 0.0000322 (1/31018), which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in multiple BTHAL-ITMD cases both as homozygotes and compound heterozygotes. In addition, multiple reputable databases classified this variant as pathogenic. Furthermore, another variant at this location, c.-78A>G has been reported and classified by LCA as "pathogenic," supporting the importance of this region/location for proper function. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "Pathogenic." -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 06, 2018	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 27, 2017	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	The HBB c.-78A>C variant (rs33931746, HbVar ID: 768), also known as -28 (A>C), is reported in the literature in individuals affected with beta thalassemia (Agouti 2008, Gamarra 2009, Perea 1996, Poncz 1982, HbVar database) or in heterozygous carriers with microcytic anemia (Gamarra 2009, Perea 1996). In several individuals with beta thalassemia major, this variant was observed in trans to a beta-0 pathogenic variant (Gamarra 2009, Perea 1996). The c.-78A>C variant is located in the TATA box of the HBB gene (Poncz 1982), and functional analyses in transfected HeLa cells suggest it leads to a 2- to 3-fold decrease in beta globin transcription (Surrey 1985). Another variant at this position, c.-78A>G, is a common beta+ pathogenic variant that leads to a 3- to 5-fold reduction in HBB transcripts (Orkin 1983, Yamsri 2011). The c.-78A>C variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Agouti I et al. Molecular basis of beta-thalassemia in Morocco: possible origins of the molecular heterogeneity. Genet Test. 2008 Dec;12(4):563-8. PMID: 18976160. Gamarra S et al. beta-Thalassaemia Major in a Spanish Patient due to a Compound Heterozygosity for CD39 C > T/-28 A > C. Adv Hematol. 2009;2009:476342. PMID: 19960060. Orkin SH et al. ATA box transcription mutation in beta-thalassemia. Nucleic Acids Res. 1983; 11(14):4727-34. PMID: 6308558. Perea FJ et al. Haplotype analysis of the Mexican frameshift Cd 11 (-T) and -28 A->C beta-thalassemia alleles. Am J Hematol. 1996 Mar;51(3):240-2. PMID: 8619407. Poncz M et al. beta-Thalassemia in a Kurdish Jew. Single base changes in the T-A-T-A box. J Biol Chem. 1982 Jun 10;257(11):5994-6. PMID: 7076659. Surrey S et al. Functional analysis of a beta-globin gene containing a TATA box mutation from a Kurdish Jew with beta thalassemia. J Biol Chem. 1985 Jun 10;260(11):6507-10. PMID: 2987224. Yamsri S et al. Genotype and phenotype characterizations in a large cohort of beta-thalassemia heterozygote with different forms of alpha-thalassemia in northeast Thailand. Blood Cells Mol Dis. 2011; 47(2):120-4. PMID: 21664157. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 19, 2023	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters HBB gene expression (PMID: 2987224, 24616209). ClinVar contains an entry for this variant (Variation ID: 15470). This variant is also known as -28 A>C. This variant has been observed in individual(s) with autosomal recessive HBB-related disease (PMID: 2200760, 8619407, 16103715, 17994378, 19960060). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). 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. -

alpha Thalassemia;C0002895: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

Jan 27, 2022

- -

Hb SS disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Beta-plus-thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 10, 1982

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	15
DANN	Benign	0.88

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs33931746; hg19: chr11-5248329;