rs33971440

chr11-5226929-C-Achr11-5226929-C-Gchr11-5226929-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong

The NM_000518.5(HBB):c.92+1G>T variant causes a splice donor 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

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

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 22 ACMG points.

PVS1

Splicing variant, LoF is a know mechanism of disease,

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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/exons	MANE	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.92+1G>T		splice_donor_variant		ENST00000335295.4

Ensembl

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

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 13, 2023	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 23, 2018	- -

beta Thalassemia

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2022	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. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 18, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

Beta zero thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 27, 2017

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2017

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. -

alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:Methemoglobinemia, beta-globin type;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 13, 2022

- -

HBB-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2023

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 20, 2021

- -

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

MutationTaster

Benign

1.0

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