chr11-5225483-TTTTTA-T

Position:

• chr11-5225483-TTTTTA-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_000518.5(HBB):​c.*110_*114delTAAAA variant causes a 3 prime UTR change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 3_prime_UTR
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 3.64

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5225483-TTTTTA-T is Pathogenic according to our data. Variant chr11-5225483-TTTTTA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15506.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-5225483-TTTTTA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.*110_*114delTAAAA		3_prime_UTR_variant	3/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295	c.*110_*114delTAAAA		3_prime_UTR_variant	3/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

beta Thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

curation

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Nov 25, 2019

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 28, 2024

The HBB c.*110_*114del variant (also known as -AATAA and c.*108_*112delAATAA) is located in the polyadenylation signal of the beta globin (HBB) mRNA. This variant prevents polyadenylation of the beta globin mRNA at the normal polyadenylation site and causes the synthesis of an elongated beta globin mRNA (PMID: 1374896 (1992)). It is associated with severe beta(+)-thalassemia (HbVar, http://globin.bx.psu.edu/cgi-bin/hbvar/counter). In the published literature, this variant has been reported in homozygous individuals affected with beta thalassemia major (PMID: 1705411 (1990), 1374896 (1992), 9140720 (1997), 24200152 (2014)). It has also been seen with Hb S in one individual (PMID: 14649318 (2003)). Variants in the delta globin (HBD) gene have also been reported in some individuals with this HBB variant (PMIDs: 24985928 (2014), 24200152 (2014)). -

Beta-plus-thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 1992

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs35949130; hg19: chr11-5246713;