NM_000518.5:c.*132C>A

Variant names:

• chr11-5225466-G-T
• rs1420779550
• NM_000518.5:c.*132C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000518.5(HBB):​c.*132C>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000176 in 850,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: HBB NM_000518.5 splice_region
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.114

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]

ENSG00000285498 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.*132C>A		splice_region_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1
HBB	NM_000518.5	c.*132C>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.*132C>A		splice_region_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3
HBB	ENST00000335295	c.*132C>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000573 AC: 4 AN: 698364 Hom.: 0 Cov.: 9 AF XY: 0.00000804 AC XY: 3 AN XY: 373098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000102

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: 0.00

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000831

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Sep 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.*132C>A variant (rs1420779550; ClinVar Variation ID: 1343492) is reported in the literature in several individuals affected with beta thalassemia intermedia that also carried a pathogenic HBB variant in trans (Heath 2001, Torre 2020). However, one of these individuals carried a second variant, c.*129T>C, in cis to the c.*132C>A variant (Heath 2001). The c.*132C>A variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant occurs in the 3’UTR but does not affect the functionally important polyadenylation signal sequence. Another variant at the same nucleotide, c.*132C>T, has also been reported in individuals affected with beta thalassemia intermedia that carried pathogenic HBB variants in trans (Bilgen 2013, Sripusanapan 2020). However, given the lack of clinical and functional data, the significance of the c.*132C>A variant is uncertain at this time. References: Bilgen T et al. Two novel mutations in the 3' untranslated region of the beta-globin gene that are associated with the mild phenotype of beta thalassemia. Int J Lab Hematol. 2013 Feb;35(1):26-30. PMID: 22862814. Heath JA et al. A novel beta-thalassemia intermedia phenotype containing Nt494+129T-->C and NT494+132C-->A mutations in cis and a Nt168C-->T (beta(o) 39 point) mutation in trans. Am J Hematol. 2001 May;67(1):57-8. PMID: 11279660. Sripusanapan A et al. Compound heterozygosity of a silent beta-thalassemia mutation at the 3'-untranslated region (HBB: c.*132 C>T) and beta-zero thalassemia results in thalassemia intermedia. Pediatr Blood Cancer. 2020 Apr;67(4):e28157. PMID: 31930713. Torre LDCR et al. Three Mexican Families with beta thalassemia intermedia with different molecular basis. Genet Mol Biol. 2020 Feb 3;42(4):e20190032. PMID: 32142096. -

Nov 25, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.*132C>A variant is located in the 3’-untranslated region (UTR) of the HBB gene, approximately 20 nucleotides downstream of the beta-globin mRNA polyadenylation site. In the published literature, this variant has been reported in individuals with beta-thalassemia intermedia who carried a beta(0)-thalassemia pathogenic variant on the opposite chromosome (PMIDs: 32142096 (2020), 11279660 (2001)). Two other variants at this position, c.*132C>T and c.*132C>G, have also been reported in compound heterozygous individuals with beta-thalassemia intermedia (PMIDs: 31930713 (2020), 22862814 (2013), 36876863 (2022)), suggesting a disruption of this nucleotide may be clinically significant. The frequency of this variant in the general population, 0.00065 (10/15284 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Uncertain:1

Feb 24, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.*132C>A is located in the untranslated mRNA region downstream of the termination codon. The variant lies about 20 nucleotides downstream to the known polyA-tail signal, and thus it would likely not interfere with cleavage of the transcript and addition of polyA tail, however it can still affect potential protein binding sites or miRNA target sites that may influence transcript expression levels. The variant allele was found at a frequency of 7.3e-05 in 150942 control chromosomes, predominantly within the Latino subpopulation at a frequency of 0.00065 in the gnomAD database (v3.1 genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.*132C>A, has been reported in the literature in two compound heterozygous Hispanic individuals, who were affected with Beta Thalassemia Intermedia, and carried a beta-0 variant in trans (Heath_2001, Rizo-de-la-Torre_2020), however, one of these individuals also carried the variant c.*129T>C in cis with the c.*132C>A variant (Heath_2001). These data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant affecting the same nucleotide, c.*132C>T, has also been reported in individuals affected with Beta Thalassemia Intermedia (PMIDs: 22862814, 31930713), suggesting that variants affecting this 3' UTR region might have functional effect. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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 Uncertain:1

Apr 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.0
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1420779550; hg19: chr11-5246696;