rs33978907

Positions:

• chr11-5225488-A-G
• chr11-5225488-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000518.5(HBB):​c.*110T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 1,014,924 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 Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: HBB NM_000518.5 3_prime_UTR
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 1.34

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 11-5225488-A-G is Pathogenic according to our data. Variant chr11-5225488-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 36332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225488-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.*110T>C		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.*110T>C		3_prime_UTR_variant	3/3	1	NM_000518.5	ENSP00000333994	P1
HBB	ENST00000647020.1	c.*110T>C		3_prime_UTR_variant	3/3			ENSP00000494175	P1
HBB	ENST00000633227.1	c.*370T>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	3		ENSP00000488004
	ENST00000644706.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 10 AN: 862568 Hom.: 0 Cov.: 12 AF XY: 0.00000441 AC XY: 2 AN XY: 453220

Gnomad4 AFR exome AF: 0.000139

Gnomad4 AMR exome AF: 0.0000238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000274

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000350

Gnomad4 OTH exome AF: 0.0000494

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74510

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000982

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	The HBB c.*110T>C variant (rs33978907, HbVar ID: 968), also known as Poly A (T->C), has been reported in multiple patients diagnosed with beta (+) thalassemia, and has been found in a homozygous state, or in-trans with other pathogenic variants (Hoppe 2013, Italia 2012, Orkin 1985, Sinha 2009, Sivalingam 2012, see link to HbVar). Functional characterization of the variant indicates the loss of the canonical polyadenylation site, resulting in an elongated HBB transcript that is less efficiently processed by a downstream cryptic polyadenylation site (Orkin 1985). This variant is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 36332), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in a conserved region of the 3' UTR, and computational algorithms (Poly A miner) predict an impact on the transcript, consistent with observations from the functional study. Based on available information, the c.*110T>C variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Hoppe CC. Prenatal and newborn screening for hemoglobinopathies. Int J Lab Hematol. 2013 Jun;35(3):297-305. PMID: 23590658. Italia K et al. Variable haematological and clinical presentation of beta-thalassaemia carriers and homozygotes with the Poly A (T?C) mutation in the Indian population. Eur J Haematol. 2012; 89(2):160-4. PMID: 22690826. 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. Sinha S et al. Profiling beta-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes. Hugo J. 2009 Dec;3(1-4):51-62. PMID: 21119755. Sivalingam M et al. Molecular study and genotype/phenotype correlation of beta thalassemia in Malaysia. Int J Lab Hematol. 2012 Aug;34(4):377-82. PMID: 22335963. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of multiple amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs33978907, gnomAD 0.03%). This variant has been observed in individuals with beta-thalassemia (PMID: 1787101, 4018033, 22335963, 22690826, 23590658). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36332). Studies have shown that this variant results in the activation of a cryptic splice site in 3' UTR (PMID: 4018033). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 11, 2021	- -

beta Thalassemia Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 05, 2020	Variant summary: HBB c.*110T>C is located in the 3UTR downstream of the termination codon involves the alteration of a conserved nucleotide. The variant of interest is located within the known "polyA' tail, thus expected to alter mRNA expression, which is supported by Orkin_1985 functional findings. The variant allele was found at a frequency of 6.4e-05 in 31396 control chromosomes (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.011). c.*110T>C has been reported in the literature in multiple individuals affected with Beta Thalassemia and implicated to be the third most common allele in India (Orkin_1985, Sinha_2009, Italia_2012). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (4x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 16, 2015	- -

Beta-thalassemia HBB/LCRB Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Feb 01, 2024

- -

Hb SS disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Beta-plus-thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1985

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.82

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: rs33978907; hg19: chr11-5246718;