chr11-5226929-C-A

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>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000279 in 1,612,762 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

HBB
NM_000518.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

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-A is Pathogenic according to our data. Variant chr11-5226929-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226929-C-A is described in Lovd as [Pathogenic]. Variant chr11-5226929-C-A 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>T		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>T		splice_donor_variant, intron_variant	Intron 1 of 2	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251366

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000588

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1460538

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

726710

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000452

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Aug 21, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 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>T variant (rs33971440, HbVar ID: 818) is predicted to cause a loss of the canonical donor splice site and has been associated with beta(0) thalassemia (see HbVar link, Kazazian 1984); therefore this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Kazazian HH Jr et al. (1984) Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 3(3):593-6. PMID: 6714226 -

Apr 01, 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 0.06%). Disruption of this splice site has been observed in individuals with autosomal recessive beta thalassemia (PMID: 9450794, 22335963, 25849334, 27263053, 29695942). It is commonly reported in individuals of South Asian ancestry (PMID: 9450794, 22335963, 27263053). This variant is also known as "IVS1-1 G-T". ClinVar contains an entry for this variant (Variation ID: 15437). 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. -

Nov 03, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in association with beta-thalassemia (Kazazian et al., 1984; Varawalla et al., 1991; Yasmeen et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8199027, 16044458, 10975438, 2064964, 26865073, 26715484, 26554253, 22975760, 25525159, 10870879, 9225979, 18294253, 26291967, 12885342, 19090545, 18759082, 19000664, 19843386, 19254853, 28635337, 6714226, 27263053, 30275481, 9629495, 31890591, 9163586, 8012089) -

beta Thalassemia

Pathogenic:4

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

- -

Dec 18, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 05, 2022

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>T 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. The variant allele was found at a frequency of 7.2e-05 in 251366 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Beta Thalassemia (7.2e-05 vs 0.011), allowing no conclusion about variant significance. c.92+1G>T has been reported in the literature in numerous individuals affected with Beta Thalassemia. These data indicate that the variant is very likely to be associated with disease. Eight 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. -

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

The variant HBB:c.92+1G>Tis beta0 type of mutation.The variant introduce a premature termination codon. When this variant present with other pathogenic HBB mutation leads to severe type of thalassemia. Patients needing blood transfusion, often presented with hepatosplenomegaly, Iron overload. The frequency of the variant among thalassemia patient in Eastern India is 0.09 % 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] -

Mar 11, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. In silico tools predict the variant to alter splicing and produce an abnormal transcript [Splice AI: 0.98 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015437 /PMID: 6714226 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Beta zero thalassemia

Pathogenic:1

Feb 27, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases

Pathogenic:1

Aug 09, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.92+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the HBB gene. This mutation was reported in an infant with beta thalassemia major in conjunction with a second HBB alteration (Garewal G et al. Am. J. Hematol., 2005 Aug;79:252-6). This mutation is a common cause of beta thalassenia and results in beta-zero thalassemia (Chan OT et al. Am. J. Clin. Pathol., 2010 May;133:700-7; Sivalingam M et al. Int J Lab Hematol, 2012 Aug;34:377-82). In addition to the clinical data presented in the literature, 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. As such, this alteration is classified as a disease-causing mutation. -

HBB-related disorder

Pathogenic:1

Dec 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HBB c.92+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, previously described as IVS I -1G>T, has been reported to be causative for beta-thalassemia with highest frequencies for the variant being found in Indian and Thai populations (Edison et al. 2008. PubMed ID: 18294253; Muhammad et al. 2017. PubMed ID: 28635337; Kazazian et al 1984. PubMed ID: 6714226; http://ccg.murdoch.edu.au/thalind/variants.php). Another substitution at the same position, c.92+1G>A, has also been found in individuals with beta-thalassemia (Faustino et al. 1992. PubMed ID: 1634236; Waye et al. 2002. PubMed ID: 11939519). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD. Variants that disrupt the consensus splice donor site in HBB are expected to be pathogenic. The c.92G>T variant is interpreted 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

Apr 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hb SS disease

Pathogenic:1

Jan 20, 2021

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

0.36

BayesDel_noAF

Pathogenic

0.42

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

0.50

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