Submissions for variant NM_000518.5(HBB):c.-10_-7del

dbSNP: rs34196559

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588894	SCV000697070	likely benign	not provided	2016-03-21	criteria provided, single submitter	clinical testing	Variant summary: c.-10_-7delAACA affects non-conserved nucleotides, resulting in deletion of 4 nucleotides in the 5UTR region. Mutation taster predicts benign outcome. 4/5 in silico toosl via Alamut predict no significant change on the RNA splicing sites, ESEfinder predicts gain of binding motif for RNA splicing enhancer. However, these predictions should be taken with caution as Alamut tools are meant to analyze UTR regions, however, based on the topology of the region around this mutation does not include any regulatory elements (Sgourou, 2004). This variant was found in 6/121126 control chromosomes at a frequency of 0.0000495, predominantly observed in East Asian subpopulation with MAF of 0.000465 (4/8604 chr), which does not exceed the maximal expected frequency of a pathogenic allele (0.0111803). This variant has been reported both in cis and trans with known b-thal-0 variants in individuals presented with b-thal trait, suggesting that the variant in interest does not contribute to the thalassemic phenotype in these pts. Moreover, 2 individual, heterozygous for the variant of interest, had normal hematological parameters, suggesting that the variant is rare benign polymorphism. Functional studies so far yielded conflicting results ranging from no effect to a minor decrease steady state levels of mRNA to 70.6% compared with the wild type gene when different experimental systems were used (Frances, 1993; Sgourou, 2004). Taking togeter, the variant is likely to be a benign polymorphism, however, more clinical data as well as results of translational studies needed to evaluate the variant with confidence. Therefore, the variant was scored as likely benign until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588894	SCV005625785	uncertain significance	not provided	2023-11-21	criteria provided, single submitter	clinical testing	The HBB c.-10_-7del variant has been reported in the published literature in several individuals suspected of thalassemia, however only limited data were available (PMIDs: 2043469 (1991), 25849334 (2015), 34659349 (2021), 35023007 (2022), 35225055 (2022), 35783323 (2022), 36246595 (2022), 36861132 (2023), 37270807 (2023)). Clinically examined asymptomatic individuals were reported in one family study. The proband son carried this variant with a pathogenic variant (in trans) and was found to be clinically asymptomatic rather than having a beta thalassemia intermedia phenotype. The mother and daughter carried this variant alone were also asymptomatic. The father who carried the pathogenic variant had a classic beta-thalassemia trait phenotype (PMID: 19066892 (2009)). This variant was also reported with other pathogenic variants (PMIDs: 32473995 (2020), 37270807 (2023)) as well as part of a complex allele in an individual affected with beta thalassemia minor (PMID: 24200214 (2014)). Experimental results were inconclusive due to one study that reported the variant to have reduced expression in murine erythroid cells (PMID: 15009072 (2004)) while another study reported no significant effect on expression in HeLa cells (PMID: 8338769 (1993)). The frequency of this variant in the general population, 0.00033 (6/18360 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect HBB mRNA splicing. Previous names for this variant include CAP +40 to +43 (-AAAC), Beta(CAP), and c.-11_-8delAAAC. Based on the available information, we are unable to determine the clinical significance of this variant.
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	RCV001078296	SCV001244456	pathogenic	beta Thalassemia	2019-11-25	no assertion criteria provided	curation
Natera, Inc.	RCV001078296	SCV002091626	likely benign	beta Thalassemia	2018-10-05	no assertion criteria provided	clinical testing