rs35724775

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000518.5(HBB):c.92+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000738 in 1,612,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 1 hom. )

Consequence

HBB
NM_000518.5 splice_donor_region, intron

Scores

Splicing: ADA: 0.9397

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: 1.09

Variant links:

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5226924-A-G is Pathogenic according to our data. Variant chr11-5226924-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226924-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.92+6T>C		splice_donor_region_variant, intron_variant		ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.92+6T>C		splice_donor_region_variant, intron_variant		1	NM_000518.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251332

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000719

AC:

105

AN:

1459904

Hom.:

Cov.:

AF XY:

0.0000854

AC XY:

AN XY:

726418

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000721

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000982

EpiCase

AF:

0.000382

EpiControl

AF:

0.000652

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:8Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000518.4(HBB):c.92+6T>C(aka IVS-I-6T>C) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-plus variant. Sources cited for classification include the following: PMID 7522523, 2200760, and 23321370. Classification of NM_000518.4(HBB):c.92+6T>C(aka IVS-I-6T>C) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	The c.92+6T>C variant (formerly known as IVS-I-6) in HBB has been reported in the homozygous state in at least 38 individuals with beta thalassemia and in the compound heterozygous state with another pathogenic HBB variant in at least 36 individuals with beta thalassemia (Jalilian 2017 PMID: 28391758, Fernandes 2011 PMID: 21797703, El-Latif 2002 PMID: 11939510, Danjou 2015 PMID: 25480500, Chen 2015 PMID: 25856402, Carrocini 2017 PMID: 28366028). It has also been identified in 0.95% (3/316) of Middle Eastern chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is still compatible with a recessive allele frequency for a common condition. This variant has also been reported in ClinVar (Variation ID 15450). This variant disrupts the canonical splice donor site of intron 1. Functional assays show that this variant results in aberrant splicing of the first and second exons of HBB, leading to production of non-functional mRNA and reduction of wildtype transcripts (Breveglieri 2015 PMID: 26097845). Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PVS1_Strong, PS3, PM3_VeryStrong. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 21, 2020	PS3, PS4, PM3, PP3, PP4, PP5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.011%). Splice region variant predicted to alter splicing. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015450). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Jul 01, 2015	Our laboratory reported dual molecular diagnoses in HBB (NM_000518.4, c.92+6T>C) and TJP2 (NM_004817.3, c.1243delT homozygous) in one individual with reported features that include prematurity, cholestasis of the liver, mild pulmonic stenosis, chronic anemia of thalassemia, and obstructive sleep apnea. The HBB variant has been previously reported as disease-causing (PMID 20395516, 21797703, 21228398). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2018	The HBB c.92+6T>C variant, widely known as IVS-I-6, is a well-described and common cause of beta thalassemia, with the greatest frequency among Mediterranean and Middle-Eastern populations, accounting for up to 48.5 percent of disease alleles in some populations (El-Latif et al. 2002; Origa et al. 2015). Individuals who are homozygous or compound heterozygous for the c.92+6T>C variant display a range of disease phenotypes from beta thalassemia intermedia to beta thalassemia major (El-Latif et al. 2002; Origa et al. 2015). Across a selection of available literature, the c.92+6T>C variant has been identified in a homozygous state in at least 42 patients and in a compound heterozygous state with a second pathogenic variant in at least 21 individuals, with symptoms ranging from non-transfusion dependent beta thalassemia to transfusion dependent beta thalassemia major (El-Latif et al. 2002; Kakavas et al. 2006; El-Gawhary et al. 2007; Bell et al. 2011). Control data are unavailable for the c.92+6T>C variant, which is reported at a frequency of 0.00046 in the Other population of the Genome Aggregation Database. RT-PCR experiments demonstrated that the c.92+6T>C variant produces aberrantly spliced mRNA transcripts in samples derived from homozygous patients or a transgenic mouse line (TG-Î²-IVSI-6) (Breveglieri et al. 2015). Haplotype analysis has also shown the c.92+6T>C variant is linked to two beta-globin cluster haplotypes, Mediterranean VI and VII (El-Latif et al. 2002; Chen et al. 2015). Based on the collective evidence, the c.92+6T>C variant is classified as pathogenic for beta thalassemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 09, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2022	Published functional studies demonstrate that this variant results in aberrantly spliced mRNAs (Breveglieri et al., 2015); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 21228398, 23348723, 25525159, 22975760, 6280057, 26097845, 25856402, 27959697, 25825561, 26372288, 28391758, 28670940, 28366028, 34426522, 31589614, 9163586, 2577233, 9629495, 34272389) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2023	The HBB c.92+6T>C variant (rs35724775, ClinVar ID: 15450, HbVar ID: 826), also known as IVS-I-6 T>C, is reported in the literature in multiple individuals affected with beta(+) thalassemia (Carrocini 2017, Hussain 2017, Jalilian 2017). This variant is one of the most common beta-thalassemia alleles in Mediterranean and Middle-Eastern countries (El-Latif 2002, HbVar database and references therein). This variant disrupts the canonical splice donor site of intron 1, and functional assays show aberrant splicing of the first and second exons of HBB, leading to production of non-functional beta globin mRNA and reduction of wildtype transcripts (Breveglieri 2015). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Breveglieri G et al. Generation and Characterization of a Transgenic Mouse Carrying a Functional Human beta-Globin Gene with the IVSI-6 Thalassemia Mutation. Biomed Res Int. 2015:687635. PMID: 26097845. Carrocini GCS et al. Mutational Profile of Homozygous beta-Thalassemia in Rio de Janeiro, Brazil. Hemoglobin. 2017 Jan;41(1):12-15. PMID: 28366028. El-Latif MA et al. The beta+-IVS-I-6 (T-->C) mutation accounts for half of the thalassemia chromosomes in the Palestinian populations of the mountain regions. Hemoglobin. 2002 Feb;26(1):33-40. PMID: 11939510. Hussain A et al. Rare beta-Globin Gene Mutations in Pakistan. Hemoglobin. 2017 Mar;41(2):100-103. PMID: 28670940. Jalilian M et al. The Frequency of HBB Mutations Among beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. PMID: 28391758. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs35724775, gnomAD 0.02%). This variant has been observed in individuals with beta thalassemia (PMID: 2200760, 7668219, 21797703, 25856402, 28366028, 28391758, 28670940). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS-1-VI and IVS-I-6 T>C. ClinVar contains an entry for this variant (Variation ID: 15450). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in alternative splicing and introduces a premature termination codon (PMID: 26097845). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2018	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 22, 2015

The c.92+6T>C (also known as IVS1-6T>C in the literature) intronic pathogenic mutation results from a T to C substitution 6 nucleotides after coding exon 1 in the HBB gene. This mutation is a prevalent pathogenic mutation in the Mediterranean population (Origa R. Beta-Thalassemia. 2000 Sep 28 [Updated 2015 May 14]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1426/). In one study of patients from three countries of the Mediterranean basin (Italy, France, Malta), this mutation was reportedly detected in conjunction with the p.Q40* (c.118C>T) pathogenic mutation in HBB in 4.1% of 890 beta-thalassemia patients (Danjou F, Haematologica 2015 Apr; 100(4):452-7). This mutation accounted for 31% of alleles in a small Brazilian beta-thalassemia population (Fernandes AC, Hemoglobin 2011 ; 35(4):358-66). Based on the supporting evidence, c.92+6T>C is interpreted as a disease-causing mutation. -

Heinz body anemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Beta-thalassemia HBB/LCRB

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Feb 01, 2024

- -

HBB-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2023

The HBB c.92+6T>C variant is predicted to interfere with splicing. This variant has previously been reported to be causative for autosomal recessive beta-thalassemia (see for example Orkin et al. 1982. PubMed ID: 6280057; Makhoul et al. 2005. PubMed ID: 15638828). This variant is reported in 0.021% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-5248154-A-G). This variant is interpreted as pathogenic. -

alpha Thalassemia;C0002895:Hb SS disease;C0005283:beta Thalassemia;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1841621:Fetal hemoglobin quantitative trait locus 1;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Malaria, susceptibility to

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 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

Apr 15, 1982

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.36

Position offset: 22

DS_DL_spliceai

0.43

Position offset: 6

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.

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