11-5227143-A-T

Position:

• chr11-5227143-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000647020.1(HBB):​c.-122T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,154 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 2.73

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5227143-A-T is Pathogenic according to our data. Variant chr11-5227143-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 869326.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chr11-5227143-A-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.5227143A>T		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000647020.1	c.-122T>A		5_prime_UTR_variant	1/3			ENSP00000494175.1
HBB	ENST00000380315.2	c.-18-104T>A		intron_variant		5		ENSP00000369671.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 6

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

beta Thalassemia Pathogenic:2

Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 23, 2024	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 15, 2022	In the published literature, the variant has been reported in a Vietnamese family with multiple members showing slightly elevated A2 and indices suggestive of Beta Thalassemia Minor (PMID: 28503568 (2017)). Functional studies report the variant is damaging to protein structure and/or function (PMIDs: 28503568 (2017) and 31395865 (2019)). Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	The HBB c.-122T>A variant (rs1272414751, HbVar ID: 3029), also known as -72 (T>A), is reported in the literature in individuals affected with beta thalassemia or in heterozygous carriers (Kircher 2019, Pirastru 2017, Xinh 2022, HbVar database), although it is not fully evident whether this variant can cause beta-thalassemia in homozygous or compound heterozygous fashion on the basis of existing literature. This variant is also reported in ClinVar (Variation ID: 869326) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in the conserved CCAAT box of the beta-globin gene promoter (Pirastru 2017), and functional analyses by luciferase reporter assay suggest a reduction in beta globin transcription, with a decrease ranging from approximately 18% (Kircher 2019) to 47% (Pirastru 2017). Based on available information, this variant is considered to be likely pathogenic. References: Kircher M et al. Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution. Nat Commun. 2019 Aug 8;10(1):3583. PMID: 31395865. Pirastru M et al. A Novel -72 (T?A) ß-Promoter Mutation Causing Slightly Elevated HbA2 in a Vietnamese Heterozygote. Biomed Res Int. 2017;2017:4537409. PMID: 28503568. Xinh PT et al. Spectrum of HBB gene mutations among 696 ß-thalassemia patients and carriers in Southern Vietnam. Mol Biol Rep. 2022 Apr;49(4):2601-2606. PMID: 35023007. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 10, 2023

Variant summary: HBB c.-122T>A (aka. -72T>A) affects a non-conserved nucleotide that is located in the untranscribed region upstream of the HBB gene region, affecting the conserved CCAAT box sequence. The variant allele was found at a frequency of 6.6e-06 in 150926 control chromosomes (gnomAD v3.1 genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-122T>A has been reported in the literature in heterozygous state in individuals who were asymptomatic or had mild anemia, with laboratory values either normal or suggestive of beta-thalassemia carrier trait (e.g. Pirastru_2017, Xinh_2022). These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. Publications also reported experimental evidence evaluating the variants impact on promotor function, and demonstrated decreased promoter activities, with activity values similar to other pathogenic variants (e.g. Pirastru_2017, Kircher_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31395865, 28503568, 35023007). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. In conclusion, further cases should be evaluated where this variant is found in homozygosity or compound heterozygous state with beta-thalassemia mutations, in order to determine the clinical significance of this variant. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.65

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1272414751; hg19: chr11-5248373;