rs34999973

Variant names:

• chr11-5227161-G-A
• rs34999973
• ENST00000647020.1:c.-140C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-5227161-G-A
• chr11-5227161-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The ENST00000647020.1(HBB):​c.-140C>T variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0000171 in 701,948 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: HBB ENST00000647020.1 5_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 3.60
• Publications: 16 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: Likely_pathogenic. The variant received 7 ACMG points.

• PP5: Variant 11-5227161-G-A is Pathogenic according to our data. Variant chr11-5227161-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 15514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.-140C>T		upstream_gene_variant		ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.-140C>T		upstream_gene_variant		1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152196 Hom.: 0 Cov.: 33

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: 7 AN: 549752 Hom.: 0 Cov.: 5 AF XY: 0.0000134 AC XY: 4 AN XY: 297404

African (AFR) AF: 0.000318 AC: 5 AN: 15704

American (AMR) AF: 0.00 AC: 0 AN: 34574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19214

East Asian (EAS) AF: 0.00 AC: 0 AN: 32182

South Asian (SAS) AF: 0.0000325 AC: 2 AN: 61482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2458

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 317042

Other (OTH) AF: 0.00 AC: 0 AN: 30216

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74350

African (AFR) AF: 0.000121 AC: 5 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00000992 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Feb 07, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate this variant significantly reduces promoter activity of the HBB protein compared to wild-type (PMID: 8874232, 31395865); This variant is associated with the following publications: (PMID: 18294253, 14555318, 27615034, 28865746, 31411089, 18076350, 25525159, 1634236, 25370867, 26096776, 12709369, 18339318, 21119755, 20301599, 31395865, 21538688, 28669403, 30277083, 29124982, 30489691, 27263053, 30626236, 30275481, 32885601, 31286593, 36054783, 33092414, 35979587, 38397898, 37529778, 36861132, 34659349, 32414341, 38112059, Bhattacharjee2023[CaseReport], 8874232) -

Jun 23, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

beta Thalassemia Pathogenic:3 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 29, 2024

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Apr 15, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Beta-thalassemia HBB/LCRB Pathogenic:2

May 07, 2024

MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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] -

May 23, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HBB-related disorder Pathogenic:1

Mar 04, 2022

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 05, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.-140C>T is located in the untranscribed region upstream of the HBB gene region. The variant allele was found at a frequency of 5.4e-05 in 18632 control chromosomes. c.-140C>T has been reported in the literature in multiple individuals affected with Beta Thalassemia Intermedia. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 18294253, 18076350, 14555318, 3457470, 23590658, 19205970, 25370867). ClinVar contains an entry for this variant (Variation ID: 15514). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Mar 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Beta-plus-thalassemia Pathogenic:1

Jul 01, 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
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.71
PhyloP100		3.6
PromoterAI		-0.24	Neutral
Mutation Taster		=39/61	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs34999973; hg19: chr11-5248391;