11-5227101-A-G

Position:

• chr11-5227101-A-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.-80T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.19

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 11-5227101-A-G is Pathogenic according to our data. Variant chr11-5227101-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 869290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227101-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.16). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.5227101A>G		intergenic_region
HBB	NM_000518.5	c.-80T>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.-80T>C		upstream_gene_variant		1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 12

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 08, 2023	Variant summary: HBB c.-80T>C is located in the untranscribed region upstream of the HBB gene region. The variant was absent in 249250 control chromosomes (gnomAD). c.-80T>C has been reported in the literature in multiple individuals affected with Beta Thalassemia (Cai_1989, Ayub_2010, Xiong_2011, Panja_2017), and some were compound heterozygous with other pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on promoter activity, finding that the variant significantly reduces gene expression (Kircher_2019). The following publications have been ascertained in the context of this evaluation (PMID: 2741940, 27828729, 20406103, 31395865, 21704277). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 09, 2024

The HBB c.-80T>C variant has been reported in the published literature to be located in the TATA box promoter region of the HBB gene which is crucial to proper RNA binding and transcription (PMID: 2741940 (1989), 28385923 (2017)). Additionally, this variant has been seen in individuals with beta thalassemia who were compound heterozygous for an additional HBB pathogenic variant, suggesting this variant plays a role in development of disease (PMID: 20406103 (2010), and HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)). The variant has been noted to lead to ineffective erythropoiesis (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Beta-plus-thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Benign	0.92

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs33980857; hg19: chr11-5248331;