11-5226929-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000518.5(HBB):c.92+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000465 in 1,612,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

HBB
NM_000518.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:31O:1

Conservation

PhyloP100: 6.79

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 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5226929-C-T is Pathogenic according to our data. Variant chr11-5226929-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226929-C-T is described in Lovd as [Pathogenic]. Variant chr11-5226929-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.92+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.92+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000955

AC:

AN:

251366

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

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:

0.000158

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000459

AC:

AN:

1460538

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

726710

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:11

Jun 30, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Also described as IVS-I-1 (G> A) due to alternate nomenclature; This variant is associated with the following publications: (PMID: 25525159, 22975760, 2200760, 25087612, 23348723, 24777453, 21228398, 8602996, 6280057, 30843739, 1634236, 1390250, 28366028, 28391758, 27199182, 31718331, 34426522, 31589614, 9586437, 31890591, 9163586, 2577233) -

Jul 10, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.92+1G>A variant (also known as IVS-I-1 G->A, rs33971440, HbVar ID: 817) is predicted to cause a loss of the canonical donor splice site and has been associated with beta(0) thalassemia in several patients (see HbVar link and references therein, Orkin 1982); therefore this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Orkin S et al. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982;296(5858):627-31. PMID: 6280057 -

Jan 13, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 1 of the HBB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs33971440, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with HBB-related conditions (PMID: 2200760, 28366028, 28391758). ClinVar contains an entry for this variant (Variation ID: 15436). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

beta Thalassemia

Pathogenic:8Other:1

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000518.4(HBB):c.92+1G>A(aka IVS-I-1) 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-zero variant. Sources cited for classification include the following: PMID 1390250, 1634236 and 6188062. Classification of NM_000518.4(HBB):c.92+1G>A(aka IVS-I-1) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.92+1G>A variant in HBB (also known as IVS-I-1 G->A) has been reported in numerous individuals with beta thalassemia (selected references Faustino 1992 PMID: 1634236, Orkin 1982 PMID: 6280057, Jalilian 2017 PMID: 28391758, Aldemir 2014 PMID: 25155404). It has been reported in CLinVar (Variation ID 15436) and has been identified in 2/15288 Latino chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. 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: PM2_Supporting, PVS1, PM3_Very Strong. -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous 5' splice site variation in intron 1 of the HBB gene that affects the invariant GT donor splice site of exon 1 was detected. The variant has previously been reported in patients with beta thalassemia. The observed variant has not been reported in the 1000 genomes and gnomAD databases and has a minor allele frequency of 0.04% in our internal database. The reference base is conserved across species. -

Apr 15, 2019

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.92+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence confirming this prediction, demonstrating that this variant abolishes correct mRNA splicing (Treisman 1983). The variant allele was found at a frequency of 9.5e-05 in 251366 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HBB causing Beta Thalassemia Major (9.5e-05 vs 0.011). The variant, c.92+1G>A, was reported in the literature and in multiple databases as a common disease variant, found in several homozygous and compound heterozygous individuals affected with Beta Thalassemia Major (e.g. Faustino 1992, Shalitin 2005, Lahiry 2008). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The splice donor variant c.92+1G>A in HBB (NM_000518.5) has been reported in multiple individuals with beta thalassemia (Aldemir O et al; Thein SL et al). The variant has been reported in ClinVar as Pathogenic. This variant affects an invariant splice nucelotide and is predicted to affect protein function. For these reasons, this variant has been classified as Pathogenic. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 22, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28391758, 28366028, 2200760). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000955). The variant is in trans with the other variant. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Beta-thalassemia HBB/LCRB

Pathogenic:5

Jun 05, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.92+1G>A variant is classified as Pathogenic (PVS1, PS4_Moderate, PP4) The HBB c.92+1G>A variant is located in a splice donor region. Computational predictions support a deleterious effect on splicing and a likely disruption of the protein reading frame and non-sense mediated decay of the resulting protein product (PVS1). One publication reports experimental evidence demonstrating that this variant abolishes correct mRNA splicing (PMID: 6188062). The variant has been reported in multiple cases with a clinical presentation of beta-thalassaemia, and homozygotes tend to be transfusion-dependent (PMID:27453201, 8602996, 2200760) (PS4_Moderate). The variant is rare in population databases (gnomAD allele frequency = 0.0052%; 8 het and 0 hom in 152224 sequenced alleles; highest frequency = 0.013%, Latino population) (PM2_Supp). The variant has been reported in dbSNP (rs33971440) and in the HGMD database: CS991412. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 15436). he clinical features of this case are highly specific for the HBB, the family history is consistent with the mode of inheritance of this condition and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4). -

May 23, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 19, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM3_STR -

Dominant beta-thalassemia

Pathogenic:1

Jun 26, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.92+1G>A, also published as IVS-I-1 G->A, variant has been reported in more than twelve individuals affected with b-thalassemia major and b-thalassemia minor (Carrocini GCS et al., PMID: 28366028; Faustino P et al., PMID: 1634236; Jalilian M et al., PMID: 28391758; Shalitin S et al., PMID: 15654898). Of those individuals, four were compound heterozygous for the variant and a pathogenic or likely pathogenic confirmed in trans and eight individuals were homozygous for the variant (Carrocini GCS et al., PMID: 28366028; Faustino, P. et al., PMID: 1634236; Jalilian M et al., PMID: 28391758; Shalitin S et al., PMID: 15654898). This variant has been reported in the ClinVar database as a pathogenic variant by 27 submitters. This variant is only observed on 24 out of 251,366 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs within the canonical splice donor site, which is predicted to cause skipping of the exon, leading to an out of frame transcript. Functional studies show that this variant abolishes correct mRNA splicing, indicating that this variant impacts protein function (Orkin SH et al., PMID: 6190800; Treisman R et al., PMID: 6188062). Another two variants in the same splicing motif, c.92+1G>T and c.92+1G>C, have been reported pathogenic (Variation IDs: 15437 and 869246). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Beta zero thalassemia

Pathogenic:1

Apr 15, 1982

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases

Pathogenic:1

Nov 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.92+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the HBB gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.01% (24/251366) total alleles studied. The highest observed frequency was 0.017% (6/34586) of Latino alleles. This variant has been identified in the homozygous state in individual(s) with beta-thalassemia (Oner, 1990; Carrocini, 2017; Jalilian, 2017) and is frequent in the Mediterranean population (Farra, 2021). Another variant impacting the same donor site (c.92+1G>T) has been identified in individual(s) with beta-zero thalassemia (Chan, 2010). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Fetal hemoglobin quantitative trait locus 1

Pathogenic:1

Jul 05, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Dominant beta-thalassemia;CN322236:Beta-thalassemia HBB/LCRB

Pathogenic:1

Oct 11, 2024

Institute of Human Genetics, Heidelberg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hb SS disease

Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

GERP RS

5.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.47

Position offset: 17

DS_DL_spliceai

0.98

Position offset: 1

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