rs281864905

Positions:

• chr11-5225486-TTA-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000518.5(HBB):​c.*110_*111del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 859,910 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: HBB NM_000518.5 3_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.45

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5225486-TTA-T is Pathogenic according to our data. Variant chr11-5225486-TTA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 632843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225486-TTA-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_*111del		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	ENST00000335295.4	c.*110_*111del		3_prime_UTR_variant	3/3	1	NM_000518.5	ENSP00000333994	P1
HBB	ENST00000647020.1	c.*110_*111del		3_prime_UTR_variant	3/3			ENSP00000494175	P1
HBB	ENST00000633227.1	c.*370_*371del		3_prime_UTR_variant, NMD_transcript_variant	3/3	3		ENSP00000488004
	ENST00000644706.1			upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000151 AC: 13 AN: 859910 Hom.: 0 AF XY: 0.0000177 AC XY: 8 AN XY: 451864

Gnomad4 AFR exome AF: 0.0000463

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000193

Gnomad4 OTH exome AF: 0.0000248

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2024	Variant summary: HBB c.*110_*111delTA is located in the untranslated mRNA region downstream of the termination codon that lies in the 'known' polyA tail signal (AATAAA) of HBB, and mutations in this region are known to reduce the synthesis of mRNA. Therefore, this variant is expected or likely to interfere with cleavage of transcript and addition of polyA tail, leading to an elongated transcript that is unstable (Orkin 1985). The variant allele was found at a frequency of 5.9e-06 in 1015192 control chromosomes (gnomAD database v4). c.*110_*111delTA has been reported twice in literature, one individual diagnosed with BTHAL and one individual having typical features of BTHAL minor (Ghanem_1992, Kimberland_1995). Ithanet lists variant as a "Globin gene causative mutation". In the same region, a variant c.*110T>C and c.*111A>G have been reported in literature as a common pathogenic variants. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 1301930, 21423179, 7599641). ClinVar contains an entry for this variant (Variation ID: 632843). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 28, 2022	The Poly A (-AT or -TA) variant (HBB: *110_*111delTA, rs63750205, HbVar ID: 972) is reported in an individual with beta-thalassemia and in an individual presenting with typical beta-thalassemia trait (Ghanem 1992, HbVar link, Kimberland 1995). This variant is also listed in ClinVar (Variation ID: 632843), and in ITHANET as a causative variant (ITHANET link). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in the untranslated mRNA region in the known polyA tail signal (AATAAA) of HBB. Other variants in this region (c.*110T>C, c.*111A>G) are common pathogenic variants shown to reduce mRNA synthesis (Orkin 1985). Based on available information, the *110_*111delTA variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Link to ITHANET database: https://www.ithanet.eu/db/ithagenes?ithaID=277 Ghanem N et al. A comprehensive scanning method for rapid detection of beta-globin gene mutations and polymorphisms. Hum Mutat. 1992;1(3):229-39. PMID: 1301930. Kimberland ML, Boehm CD, Kazazian HH Jr. Two novel beta-thalassemia alleles: poly A signal (AATAAA-->AAAA) and -92 C-->T. Hum Mutat. 1995;5(3):275-6. PMID: 7599641. Orkin S et al. Thalassemia due to a mutation in the cleavage-polyadenylation signal of the human beta-globin gene. EMBO J. 1985; 4(2):453-6. PMID: 4018033. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 08, 2021	The variant disrupts the canonical polyadenylation signal, and is therefore predicted to result in the loss of a functional protein. The variant is found in at least one symptomatic individual, and not found in general population data. -

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: rs63750205; hg19: chr11-5246716;