rs34196559

Variant names:

• chr11-5227027-CTGTT-C
• rs34196559
• NM_000518.5:c.-10_-7delAACA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000518.5(HBB):​c.-10_-7delAACA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,423,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: HBB NM_000518.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: 0.544

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-5227027-CTGTT-C is Benign according to our data. Variant chr11-5227027-CTGTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495971.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.-10_-7delAACA		5_prime_UTR_variant	Exon 1 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.-10_-7delAACA		5_prime_UTR_variant	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251080 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000197 AC: 28 AN: 1423342 Hom.: 0 AF XY: 0.0000113 AC XY: 8 AN XY: 710602

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 32622

Gnomad4 AMR exome AF: 0.0000224 AC: 1 AN: 44694

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25886

Gnomad4 EAS exome AF: 0.000152 AC: 6 AN: 39580

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85714

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53396

Gnomad4 NFE exome AF: 0.0000186 AC: 20 AN: 1076658

Gnomad4 Remaining exome AF: 0.0000169 AC: 1 AN: 59120

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

beta Thalassemia Pathogenic:1 Benign:1

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 05, 2018

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Nov 21, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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. -

not specified Benign:1

Mar 10, 2025

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.-10_-7delAACA is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 4e-05 in 251080 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Beta Thalassemia (4e-05 vs 0.011), allowing no conclusion about variant significance. c.-10_-7delAACA has been reported both in cis and trans with pathogenic variants (such as, HBB c.126_129delCTTT) in individuals presented with Beta-Thalassemia trait, suggesting this variant does not contribute to the thalassemic phenotype in these patients (Xinh_2022, Huang_1991, Zhang_2015, LiDZ_2009). Moreover, 2 individuals, heterozygous for the variant of interest, had normal hematological parameters, suggesting that the variant is rare benign polymorphism (Huang_2013). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Sgourou_2004, Frances_1993). The following publications have been ascertained in the context of this evaluation (PMID: 8338769, 2043469, 24200214, 25849334, 15009072, 26715484, 19066892, 35023007). ClinVar contains an entry for this variant (Variation ID: 495971). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

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: rs34196559; hg19: chr11-5248257;