rs35949130

Variant names:

• chr11-5225483-TTTTTA-T
• rs35949130
• NM_000518.5:c.*110_*114delTAAAA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

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: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.64
• Publications: 1 publications found

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]

HBB Gene-Disease associations (from GenCC):

• dominant beta-thalassemia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• hemoglobin M disease

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
• beta thalassemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• beta-thalassemia HBB/LCRB

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• erythrocytosis, familial, 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Heinz body anemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• sickle cell disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia intermedia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia major

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• delta-beta-thalassemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-beta-thalassemia disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin c disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin d disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin E disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 15506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.*110_*114delTAAAA		3_prime_UTR_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.*110_*114delTAAAA		3_prime_UTR_variant	Exon 3 of 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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB: c.*110_*114del variant, (rs35949130, HbVar ID: 973, ClinVar ID: 15506) is reported homozygous in the literature in multiple individuals with transfusion dependent beta thalassemia major (Colaco 2014, Lacan 2003, Rund 1992). This variant has also reported compound heterozygous with Hb S in an individual with beta+ -thalassemia. This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant occurs in the 3' untranslated region and results in the deletion of the majority of the poly(a) signal. Functional characterization indicates the complete loss of cleavage at the canonical polyadenylation site, resulting in an elongated HBB transcript that is less efficiently processed by a downstream cryptic polyadenylation site (Rund 1992). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Colaco S et al. Masking of a ß-thalassemia determinant by a novel d-globin gene defect [Hb A2-Saurashtra or d100(G2)Pro?Ser; HBD: c.301C>T] in Cis. Hemoglobin. 2014;38(1):24-7. PMID: 24200152. Lacan P et al. Mild Hb S-beta(+)-thalassemia with a deletion of five nucleotides at the polyadenylation site of the beta-globin gene. Hemoglobin. 2003 Nov;27(4):257-9. PMID: 14649318. Rund D et al. Two mutations in the beta-globin polyadenylylation signal reveal extended transcripts and new RNA polyadenylylation sites. Proc Natl Acad Sci USA. 1992 May 15;89(10):4324-8. PMID: 1374896. -

Mar 28, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 Thalassemia Pathogenic: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

- -

Beta-plus-thalassemia Pathogenic:1

May 15, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=35/65	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs35949130; hg19: chr11-5246713;