11-5225832-G-C

Variant names:

• chr11-5225832-G-C
• rs34690599
• NM_000518.5:c.316-106C>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000518.5(HBB):​c.316-106C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,168,954 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 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: HBB NM_000518.5 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22 O:1
• Conservation: PhyloP100: -0.634

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-5225832-G-C is Pathogenic according to our data. Variant chr11-5225832-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225832-G-C is described in Lovd as [Pathogenic]. Variant chr11-5225832-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.316-106C>G		intron_variant	Intron 2 of 2	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.316-106C>G		intron_variant	Intron 2 of 2	1	NM_000518.5	ENSP00000333994.3
HBB	ENST00000647020.1	c.316-106C>G		intron_variant	Intron 2 of 2			ENSP00000494175.1
HBB	ENST00000475226.1	n.248-106C>G		intron_variant	Intron 1 of 1	2
HBB	ENST00000633227.1	n.*132-106C>G		intron_variant	Intron 2 of 2	3		ENSP00000488004.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 33

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000266 AC: 27 AN: 1016752 Hom.: 0 AF XY: 0.0000305 AC XY: 16 AN XY: 524838

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000337

Gnomad4 OTH exome AF: 0.0000438

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

Gnomad4 AFR AF: 0.00

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: 0.0000735

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:8

Feb 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 2 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 55 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with β-thalassemia (PMID: 2713503, 11559932, 23425204, 25155404). This variant is also known as IVS-II-745C>G or IVS2-745C>G. ClinVar contains an entry for this variant (Variation ID: 15457). Studies have shown that this variant alters HBB gene expression (PMID: 6188062). Studies have shown that this variant results in the activation of a cryptic splice site in intron 2 (PMID: 6188062). For these reasons, this variant has been classified as Pathogenic. -

Jan 15, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 2375910, 28399358, 22975760, 19657842, 6280057, 23425204, 2200760, 25408857, 36882369, 32860008, 11559932, 2713503, 25155404, 9163586, 6188062) -

Jul 05, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HBB: PM2, PP4:Moderate, PS4:Moderate, PP3 -

Nov 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.316-106C>G variant (rs34690599, HbVar ID: 891), also known as IVS-II-745 C>G, is reported in the heterozygous state in individuals with beta(+) thalassemia minor and in the homozygous and compound heterozygous state in individuals with transfusion-dependent beta-thalassemia major (Orkin 1982, Ropero 2013, HbVar database). Functional characterization of the variant indicates an accumulation of beta globin transcript containing intron 2 sequences (Orkin 1982). This variant is also reported in ClinVar (Variation ID: 15457). This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant impacts splicing by creating a cryptic donor splice site, consistent with the observed phenotype in functional studies. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Orkin S et al. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982; 296(5858):627-31. PMID: 6280057. Ropero P et al. Association in cis of the mutations +20 (C>T) in the 5' untranslated region and IVS-II-745 (C>G) on the beta-globin gene. Hemoglobin. 2013; 37(2):112-8. PMID: 23425204. -

Jun 08, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 28, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

beta Thalassemia Pathogenic:5 Other:1

Aug 18, 2011

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Nov 03, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 09, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000518.4(HBB):c.316-106C>G(aka IVS2-745C>G) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-plus variant. Sources cited for classification include the following: PMID 11559932 and 6188062. Classification of NM_000518.4(HBB):c.316-106C>G(aka IVS2-745C>G) 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. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Beta-thalassemia HBB/LCRB Pathogenic:4

Jun 02, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Intron variant: previously reported to alter splicing (PMID: 6188062). Intron variant: previously reported to alter splicing (PMID: 6188062). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 05, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with HBB-related hemoglobinopathies, including beta thalassemia (OMIM). Dominant negative is also a suggested mechanism (PMID: 29700171). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable severity has been reported in sickle cell patients carrying the same variants (PMID: 31788855). In addition, clinical severity of beta-thalassemia patients is also dependent on whether variants in HBB are heterozygous, homozygous or compound heterozygous, and the amount of residual protein that is expressed (PMID: 20301599). (I) 0217 - Non-coding variant with known effect. RNA studies on transfected cells have shown that this variant creates a cryptic splice site within intron 2 leading to retention of 165bps of the intronic sequence (PMID: 6188062). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. It is one of the most common pathogenic Mediterranean variants in this gene and has been reported as homozygous or compound heterozygous in individuals with beta-thalassemia (PMIDs: 20301599, 31903828). This variant has also been reported in individuals with sickle cell disease when in compound heterozygous with the HbS variant (PMID: 31788855). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dominant beta-thalassemia Pathogenic:1

Feb 21, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2, PM3, PP4, PP5. -

HBB-related disorder Pathogenic:1

May 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HBB c.316-106C>G variant is predicted to interfere with splicing. This variant (also described as "IVS-II-745 C>G") has been reported in the heterozygous, compound heterozygous, and homozygous states in multiple individuals with beta thalassemia (Baysal et al. 1992. PubMed ID: 1390250; Sadiq et al. 2001. PubMed ID: 11559932; Ropero et al. 2013. PubMed ID: 23425204; Carrocini et al. 2017. PubMed ID: 28366028; Amin et al. 2020. PubMed ID: 33335418). It has also been observed to co-segregate with disease in a large, multi-generational family from the North Caucasus region currently living in Cyprus (Ergoren et al. 2021. PubMed ID: 33987626). Transcriptional analysis found that this variant leads to the formation of a cryptic splice donor site resulting in the insertion of 55 amino acid residues into the beta-globin mRNA (Treisman et al. 1983. PubMed ID: 6188062). This variant has not been reported in the gnomAD database, indicating this variant is rare. This 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

May 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hb SS disease Pathogenic:1

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Beta-plus-thalassemia Pathogenic:1

Apr 15, 1982

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.68
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.72		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34690599; hg19: chr11-5247062;