rs33960103

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000335295.4(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. 3/3 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
ENST00000335295.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

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.

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 ENST00000335295.4

PM2

Very rare variant in population databases, with high coverage;

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

MetaRNN computational evidence supports a deleterious effect, 0.942

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	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.92G>C	p.Arg31Thr	missense_variant, splice_region_variant	1/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.92G>C	p.Arg31Thr	missense_variant, splice_region_variant	1/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152226

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:

0.000620

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:

AN:

251362

Hom.:

AF XY:

0.000155

AC XY:

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:

AN:

1460506

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

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:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

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.:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:7

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	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Sep 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 18, 2016	Variant 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, no assertion criteria provided	literature only	OMIM	Feb 01, 1989	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Jan 26, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 15, 2021	This 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 submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	This 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2023	The 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. -

Beta-thalassemia HBB/LCRB

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN	May 07, 2024	The variant HBB:c.92G>C is a beta zero type of mutation. Functional characterized by aberrant splicing by altering the splice donar site. When this variant present in homozygous or in compound heterozygous with other beta 0 / beta + mutation leads to severe type of thalassemia. Patients needing monthly transfusion, often presented with hepatosplenomegaly, Iron overload. The frequency of the variant in thalassemia patient in Eastern India is 1.89 % 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] -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg 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. -

HBB-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2024

The HBB c.92G>C variant is predicted to result in the amino acid substitution p.Arg31Thr. In the literature, this variant is also referred to as p.Arg30Thr. This variant occurs at the splice boundary between exon 1 and intron 1, has been reported to result in aberrant splicing, has been reported to be causative for Beta-thalassemia in the presence of a second pathogenic allele (Vidaud et al. 1989. PubMed ID: 2915972; Banerjee et al. 1993. PubMed ID: 7505125). This variant is reported in 0.078% of alleles in individuals of South Asian descent in gnomAD and is reported to be pathogenic by several other lab (https://www.ncbi.nlm.nih.gov/clinvar/variation/15234/). This variant is interpreted as pathogenic. -

Beta-thalassemia major

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Feb 16, 2021

- -

Hb SS disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

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

LIST_S2

Benign

0.74

.;T;T;T

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.6

H;H;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.70

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

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.

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