Variant rs34999973 details in Genebe, Genetics Data Aggregator

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 links:

(HGNC:):

links:

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5227161-G-A is Pathogenic according to our data. Variant chr11-5227161-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227161-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
	use as main transcript	n.5227161G>A		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000647020.1 linkuse as main transcript	c.-140C>T		5_prime_UTR_variant	1/3			ENSP00000494175.1		P68871
HBB	ENST00000380315.2 linkuse as main transcript	c.-18-122C>T		intron_variant		5		ENSP00000369671.2		F8W6P5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000127

AC:

AN:

549752

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

297404

show subpopulations

Gnomad4 AFR exome

AF:

0.000318

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000325

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2019	Published functional studies demonstrate this variant significantly reduces promoter activity of the HBB protein compared to wild-type (Faustino et al., 1996; Kircher et al., 2019); This variant is associated with the following publications: (PMID: 32885601, 30275481, 27615034, 30626236, 27263053, 30489691, 29124982, 30277083, 28865746, 28669403, 21538688, 31395865, 20301599, 21119755, 18339318, 12709369, 8874232, 26096776, 25370867, 1634236, 25525159, 18294253, 14555318, 31411089, 18076350) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 04, 2023	The HBB c.-140C>T variant (rs34999973, HbVar ID: 754), also known as -90C>T, is reported in the literature in multiple individuals with hematological profiles consistent with beta-thalassemia minor (Faustino 1992, Jia 2003, Prajantasen 2014, Shaji 2003, Yan 2015) and has been reported in trans to a pathogenic HBB variant in an individual with beta-thalassemia intermedia (Prajantasen 2014). This variant is reported in ClinVar (Variation ID: 15514). It is only found on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant occurs in the HBB promoter in a conserved CACCC box necessary for efficient transcription (Myers 1986). In vitro assays show that the variant disrupts binding of an EKLF transcription factor to the CACCC box in the promoter (Faustino 1996) and results in decreased HBB expression (Jia 2003). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Faustino P et al. beta-Thalassemia mutation at -90C-->T impairs the interaction of the proximal CACCC box with both erythroid and nonerythroid factors. Blood. 1996 Oct 15;88(8):3248-9. Faustino P et al. Novel promoter and splice junction defects add to the genetic, clinical or geographic heterogeneity of beta-thalassaemia in the Portuguese population. Hum Genet. 1992 Jul;89(5):573-6. Jia S et al. A rare beta-thalassaemia mutation (C-T) at position -90 of the beta-globin gene discovered in a Chinese family. Haematologica. 2003 Oct;88(10):1191-3. Myers RM et al. Fine structure genetic analysis of a beta-globin promoter. Science. 1986 May 2;232(4750):613-8. Prajantasen T et al. Molecular characterization of a beta-thalassemia intermedia patient presenting inferior vena cava thrombosis: interaction of the beta-globin erythroid Kruppel-like factor binding site mutation with Hb E and alpha(+)-thalassemia. Hemoglobin. 2014;38(6):451-3. Shaji RV et al. Rapid detection of beta-globin gene mutations and polymorphisms by temporal temperature gradient gel electrophoresis. Clin Chem. 2003 May;49(5):777-81. Yan JM et al. Heterozygous beta-thalassemia with complete absence of hemoglobin A2 in a Chinese adult. Int J Lab Hematol. 2015 Dec;37(6):e147-9. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 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. This variant is present in population databases (rs34999973, gnomAD 0.02%). This variant has been observed in individual(s) with autosomal recessive beta thalassemia (PMID: 25370867, 27828729). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as -90C>T. ClinVar contains an entry for this variant (Variation ID: 15514). Studies have shown that this variant alters HBB gene expression (PMID: 8874232, 14555318). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 23, 2021	The variant found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant has been shown to be damaging to protein function(s) relevant to disease mechanism. The variant has been shown to be statistically associated with disease in multiple families. -

beta Thalassemia

Pathogenic:3Other:1

Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 15, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Feb 29, 2024	- -

Beta-thalassemia HBB/LCRB

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN	May 07, 2024	HBB:c.-140C>T variant present in 5' UTR of HBB gene, beta0 type of mutation. The variant probably decrease the transcription of HBB gene by altering the binding site of transcription factors. The frequency of the variant in thalassemia patient in Eastern India is 0.99 % as per our multicentric project - A Genetic Diagnostic Algorithm Based Study for Thalassemia in Northern and Eastern Indian Populations", Funded by Dept. of Biotechnology , Govt of India [Project No. BT/PR26461/MED/12/821/2018] -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 23, 2022	- -

HBB-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 04, 2022

The HBB c.-140C>T variant occurs in an intron and results in the substitution of a cytosine at nucleotide position c.-140 with a thymine. Across a selection of the available literature, the c.-140C>T variant, also referred to as c.-90C>T variant in the literature, has been reported in multiple individuals with mild beta-thalassemia (Faustino et al. 1992; Shaji et al. 2003; Li et al. 2008; Yasmeen et al. 2016; Qian et al. 2020; Origa et al. 2021) and in a compound heterozygous state in an individual with beta-thalassemia intermedia (Prajantasen et al. 2014). The highest frequency of this allele in the Genome Aggregation Database is 0.00012 in the African/African-American population (version 3.1.2). The c.-140C>T variant resides in the proximal CACCC box of the 13-globin gene promoter and in vitro experiments in HeLa cells suggest that the variant resulted in an eightfold decrease of the transcription level of the reporter gene compared to the wild-type promoter. Furthermore, mutant cells show impaired binding of EKLF to CACCC box compared to cells expressing wild-type promoter (Faustino et al. 1996; Kircher et al. 2019). Based on the available evidence, the c.-140C>T variant is classified as pathogenic for HBB-related disorders. -

Beta thalassemia intermedia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 08, 2015

- -

Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 20, 2024

- -

Beta-plus-thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.71

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs34999973

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over