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rs33960103

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000518.5(HBB):c.92G>C(p.Arg31Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000422 in 1,612,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense, splice_region

Scores

14
2
2
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000518.5
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-5226930-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 36337.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 11-5226930-C-G is Pathogenic according to our data. Variant chr11-5226930-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 15234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226930-C-G is described in Lovd as [Pathogenic]. Variant chr11-5226930-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBBNM_000518.5 linkuse as main transcriptc.92G>C p.Arg31Thr missense_variant, splice_region_variant 1/3 ENST00000335295.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBBENST00000335295.4 linkuse as main transcriptc.92G>C p.Arg31Thr missense_variant, splice_region_variant 1/31 NM_000518.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152226
Hom.:
0
Cov.:
32
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:
0.000620
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000103
AC:
26
AN:
251362
Hom.:
0
AF XY:
0.000155
AC XY:
21
AN XY:
135840
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:
0.000784
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000445
AC:
65
AN:
1460506
Hom.:
0
Cov.:
33
AF XY:
0.0000688
AC XY:
50
AN XY:
726670
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000661
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152226
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74370
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:
0.000620
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000312
Hom.:
0
ExAC
AF:
0.0000906
AC:
11

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

beta Thalassemia Pathogenic:7
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 01, 1989- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Mar 17, 2017- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, BC Children's and BC Women's HospitalsSep 12, 2023- -
Pathogenic, criteria provided, single submitterliterature onlyCounsylJan 26, 2015- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 18, 2016Variant summary: The HBB c.92G>C (p.Arg31Thr) variant involves the alteration of a conserved nucleotide located adjacent to the splice donor site in intron 1 (located in the last nucleotide of exon 1). 5/5 in silico tools predict a damaging outcome for this variant along with 5/5 splice site tools predicting the variant to inhibit the utilization of the normal splice site in intron 1. These predictions have been confirmed by functional studies demonstrating the variant to virtually abolish (98% inhibition) the utilization of the normal 5' splice site in intron 1.This variant was found in 11/121334 control chromosomes at a frequency of 0.0000907, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). It was observed in several b-thalassemia patients in either homozygosity or in compound heterozygosity with other pathogenic variants, indicating pathogenicity. In addition, multiple clinical diagnostic laboratories and reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesDec 03, 2017- -
Pathogenic, no assertion criteria providedcurationThe ITHANET community portal, The Cyprus Institute of Neurology and GeneticsNov 25, 2019- -
not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 21, 2021- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoNov 15, 2021This variant disrupts normal splicing of the beta-globin mRNA and is associated with beta(0)-thalassemia (PMIDs: 2915972 (1989), 9140720 (1997), 18056002 (2007), 23350016 (2013), 27263053 (2016), and 27828729 (2017)). 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. -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 15, 2023The Hb Monroe variant (HBB: c.92G>C; p.Arg31Thr, also known as Arg30Thr when numbered from the mature protein, rs33960103, HbVar ID: 290) has been reported in multiple patients diagnosed with beta(0) thalassemia (Vidaud 1989, HbVar database and references therein). Functional characterization of the variant indicates aberrant splicing of the beta globin RNA, resulting in severe reductions of full-length transcripts (Vidaud 1989, Agrawal 2007). This variant is found in the general population with an overall allele frequency of 0.01% (26/251362 alleles) in the Genome Aggregation Database. This variant is located adjacent to the exon-intron junction, and computational analyses predict that the variant affects the canonical splice donor (Alamut v.2.11). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Agrawal M et al. Missense mutation of the last nucleotide of exon 1 (G->C) of beta globin gene not only leads to undetectable mutant peptide and transcript but also interferes with the expression of wild allele. Haematologica. 2007 92(12):1715-6. PMID: 18056002. Vidaud M et al. A 5' splice-region G----C mutation in exon 1 of the human beta-globin gene inhibits pre-mRNA splicing: a mechanism for beta+-thalassemia. Proc Natl Acad Sci U S A. 1989 86(3):1041-5. PMID: 2915972. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 07, 2024This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 31 of the HBB protein (p.Arg31Thr). This variant is present in population databases (rs33960103, gnomAD 0.08%). This missense change has been observed in individuals with autosomal recessive beta thalassemia (PMID: 27828729). This variant is also known as p.Arg30Thr and Hb Monroe. ClinVar contains an entry for this variant (Variation ID: 15234). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HBB function (PMID: 2915972, 18056002). 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 HBB/LCRB Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The amino acid Arg at position 31 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. This sequence change replaces arginine with threonine at codon 31 of the HBB protein (p.Arg31Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. This variant has been observed in several individuals affected with beta thalassemia (Panja A et al). This variant is reported with the allele frequency (0.01034%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg31Thr in HBB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Beta-thalassemia major Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingKasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, IndiaFeb 16, 2021- -
Hb SS disease Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.55
Cadd
Pathogenic
35
Dann
Uncertain
0.99
DEOGEN2
Benign
0.13
T;T;.;T
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.98
D
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.6
H;H;.;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-4.4
D;.;.;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;.;.;D
Sift4G
Pathogenic
0.0010
D;.;.;.
Polyphen
1.0
D;D;.;.
Vest4
0.81
MutPred
0.86
Gain of catalytic residue at R31 (P = 0.1392);Gain of catalytic residue at R31 (P = 0.1392);Gain of catalytic residue at R31 (P = 0.1392);Gain of catalytic residue at R31 (P = 0.1392);
MVP
0.98
MPC
0.29
ClinPred
0.96
D
GERP RS
5.2
Varity_R
0.91
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.83
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.45
Position offset: 16
DS_DL_spliceai
0.83
Position offset: 0

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.

Other links and lift over

dbSNP: rs33960103; hg19: chr11-5248160; COSMIC: COSV58942075; COSMIC: COSV58942075; API