rs35004220

Positions:

chr11-5226820-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000518.5(HBB):c.93-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,608,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

HBB
NM_000518.5 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29O:1

Conservation

PhyloP100: -0.0740

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 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5226820-C-T is Pathogenic according to our data. Variant chr11-5226820-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226820-C-T is described in Lovd as [Pathogenic]. Variant chr11-5226820-C-T is described in Lovd as [Pathogenic]. Variant chr11-5226820-C-T 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.93-21G>A		intron_variant		ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.93-21G>A		intron_variant		1	NM_000518.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

250944

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000300

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000125

AC:

182

AN:

1456086

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

724710

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000127

Gnomad4 OTH exome

AF:

0.000349

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000226

Hom.:

Bravo

AF:

0.000174

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:29Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:9Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 12, 2021	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The c.93-21G>A variant in HBB, also known as IVS-I-110 G>A, has been reported in numerous individuals with beta-thalassemia and is one of the most common beta-thalassemia alleles in Mediterranean and Middle-Eastern countries (Kaplan 1990 PMID: 1967205, (Carrocini 2017 PMID: 28366028, Hussain 2017 PMID: 28670940, Jalilian 2017 PMID: 28391758, Baysal 1992 PMID: 1390250) https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=827). It has also been reported in ClinVar (Variation ID 15454) and has been identified in 14/68028 European chromosomes by gnomAD (https://gnomad.broadinstitute.org). In vitro functional studies support an impact on splicing (Busslinger 1981 PMID: 6895866). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PS3_Moderate, PM3_very strong. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The heterozygous c.93-21G>A variant in HBB was identified by our study in four affected members of one family with beta thalassemia. The c.93-21G>A variant in HBB has been identified in over 160 individuals with beta thalassemia (‚Äã‚ÄãPMID: 6264477, PMID: 6264391, PMID: 24106605, PMID: 28391758, PMID: 1390250, PMID: 2200760), but has been identified in 0.03% (37/128830) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs35004220). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 15454) and has been interpreted as pathogenic by multiple submitters. Of these 160 individuals, 138 were homozygotes (PMID: 1390250, PMID: 28391758, PMID: 24106605, PMID: 2200760), and 11 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 2200760, ClinVar Variation ID: 15436, ClinVar Variation ID: 15402, ClinVar Variation ID: 15457, ClinVar Variation ID: 15239; PMID: 6264391, ClinVar Variation ID: 15060; PMID: 24106605, ClinVar Variation ID: 15402, ClinVar Variation ID: 15415), which increases the likelihood that the c.93-21G>A variant is pathogenic. RT-PCR analysis of RNA from affected tissue shows evidence of altered splicing of exon 2, resulting in 19bp insertion, frameshift, and premature truncation (PMID: 16421096); altered splicing was also seen in HeLa cells (PMID: 6895866) and in a humanized mouse model (PMID: 16421096). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PS3, PM2_Supporting, PM3_VeryStrong (Richards 2015). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_000518.4(HBB):c.93-21G>A is classified as pathogenic and is associated with beta thalassemia. Sources cited for classification include the following: PMID 2200760, 1390250, 8330981, 1967205, 1390250, 2200760, 6264477, 6264391. Classification of NM_000518.4(HBB):c.93-21G>A is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Apr 06, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Molecular Hematology, Schneider Children's Medical Center of Israel	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28391758, 28366028, 2200760). It was observed to be in trans with the other variant (3billion dataset). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015454). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001668). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	HBB: PM3:Very Strong, PM2, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2021	In vitro RNA and functional studies demonstrate a damaging effect with the creation of an alternative splice site causing abnormal gene splicing (Busslinger et al., 1981).; Also known as IVS-I-110G>A; This variant is associated with the following publications: (PMID: 6264391, 21797703, 25087612, 22975760, 28670940, 27979672, 31456457, 31130284, 21228398, 26372288, 1967205, 26016902, 1390250, 6895866, 6264477, 28391758, 28366028, 28667000, 14555304, 9163586, 31589614, 15609277, 9629495, 12702481, 2577233) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs35004220, gnomAD 0.03%). This variant has been observed in individual(s) with HBB-related conditions (PMID: 1967205, 2200760, 28366028, 28391758). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS-I-110G>A. ClinVar contains an entry for this variant (Variation ID: 15454). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2023	The HBB c.93-21G>A variant (rs35004220, ClinVar ID: 15454, HbVar ID: 827), also known as IVS-I-110 G>A, is reported in the literature in multiple individuals affected with beta+ thalassemia (Carrocini 2017, Hussain 2017, Jalilian 2017). This variant is one of the most common beta-thalassemia alleles in Mediterranean and Middle-Eastern countries (Kaplan 1990, HbVar database and references therein). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Carrocini GCS et al. Mutational Profile of Homozygous beta-Thalassemia in Rio de Janeiro, Brazil. Hemoglobin. 2017 Jan;41(1):12-15. PMID: 28366028. Hussain A et al. Rare beta-Globin Gene Mutations in Pakistan. Hemoglobin. 2017 Mar;41(2):100-103. PMID: 28670940. Jalilian M et al. The Frequency of HBB Mutations Among beta-Thalassemia Patients in Hamadan Province, Iran. Hemoglobin. 2017 Jan;41(1):61-64. PMID: 28391758. Kaplan F et al. Beta-thalassemia genes in French-Canadians: haplotype and mutation analysis of Portneuf chromosomes. Am J Hum Genet. 1990 46(1):126-32. PMID: 1967205. -

Beta-thalassemia HBB/LCRB

Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 17, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2015

The c.93-21G>A pathogenic mutation (also known as IVS1-110G>A), located in coding intron 1 of the HBB gene, results from a G>A substitution 21 nucleotides before coding exon 2. This mutation was first described in an individual of Turkish Cypriot origin with severe thalassemia intermedia who was compound heterozygous for another pathogenic HBB mutation (Westaway D, Williamson R. Nucleic Acids Res. 1981;9:1777-1788). In a population of Turkish patients affected with beta thalassemia major, 33 individuals were homozygous for this pathogenic mutation and the allele frequency in some Turkish subpopulations is as high as 75% of disease alleles (Fettah A et al. Mediterr J Hematol Infect Dis. 2013;5(1):e2013055 and Baysal et al. Br J Haematol. 1992;81(4):607-9. ). RT-PCR studies from mRNA in both human samples and mouse models demonstrated the presence of aberrant splicing, with 90% of transcripts with abnormal splicing in homozygous mice (Vadolas J. J Biol Chem. 2006 Mar 17;281(11):7399-405). Based on the supporting evidence, c.93-21G>A is interpreted as a disease-causing mutation. -

Fetal hemoglobin quantitative trait locus 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

This variant was identified as compound heterozygous. -

alpha Thalassemia;C0002895:Hb SS disease;C0005283:beta Thalassemia;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1841621:Fetal hemoglobin quantitative trait locus 1;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Malaria, susceptibility to

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

Beta-thalassemia major

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Hb SS disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Beta-plus-thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1990

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.6

DANN

Benign

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.44

Position offset: -2

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