NM_000518.5(HBB):c.93-1G>C AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 16, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000506434.18

Allele description [Variation Report for NM_000518.5(HBB):c.93-1G>C]

NM_000518.5(HBB):c.93-1G>C

Genes:

LOC106099062:HBB recombination region [Gene]
HBB:hemoglobin subunit beta [Gene - OMIM - HGNC]
LOC107133510:origin of replication at HBB [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.4

Genomic location:

Preferred name:

NM_000518.5(HBB):c.93-1G>C

Other names:

IVS I-130 G>C

HGVS:

NC_000011.10:g.5226800C>G
NG_000007.3:g.70816G>C
NG_042296.1:g.331C>G
NG_046672.1:g.4735C>G
NG_059281.1:g.5272G>C
NM_000518.5:c.93-1G>CMANE SELECT
LRG_1232t1:c.93-1G>C
LRG_1232:g.5272G>C
NC_000011.9:g.5248030C>G
NM_000518.4:c.93-1G>C
p.?

Nucleotide change:

IVS1AS, G-C, -1

Links:

OMIM: 141900.0418; dbSNP: rs33943001

NCBI 1000 Genomes Browser:

rs33943001

Molecular consequence:

NM_000518.5:c.93-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Protein Links for Nucleotide (Select 589532470) (81)
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Assembly for Nucleotide (Select 589534234) (1)
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Acinetobacter sp. 694762
Acinetobacter sp. 694762
Comparative genomics and transcriptomics to identify genetic mechanisms underlying the emergence of carbapenem resistant Acinetobacter baumannii (CRAb)

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BioProject Links for Nucleotide (Select 589532060) (1)
BioProject
acid phosphatase type 7 [Dipodomys spectabilis]
acid phosphatase type 7 [Dipodomys spectabilis]
gi|2072394922|ref|XP_042524137.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000601335	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Aug 12, 2021)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 1517108, 28670940, 28391758, 32190157, 1577489, 23510507, 26182339, 27828729, 26467025
SCV001474478	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Jan 21, 2020)	germline	clinical testing	Citation Link,
SCV003439603	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 16, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 2283297, 9163586, 28391758, 28670940, 16199547, 23637309, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000601335

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Aug 12, 2021)

unknown

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV001474478

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Jan 21, 2020)

germline

clinical testing

Citation Link,

SCV003439603

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 16, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Two beta-thalassemia mutations in Japan: codon 121 (GAA----TAA) and IVS-I-130 (G----C).

Yamamoto K, Yamamoto K, Hattori Y, Yamashiro Y, Hoshitani M, Morishita M, Ohba Y, Katahira H, Karasawa M, Omine M, et al.

Hemoglobin. 1992;16(4):295-302. No abstract available.

PubMed [citation]

PMID:: 1517108

Identification of seven novel variants in the β-globin gene in transfusion-dependent and normal patients.

Aldakeel SA, Ghanem NZ, Al-Amodi AM, Osman AK, Al Asoom LI, Ahmed NR, Almandil NB, Akhtar MS, Azeez SA, Borgio JF.

Arch Med Sci. 2020;16(2):453-459. doi: 10.5114/aoms.2019.84825.

PubMed [citation]

PMID:: 32190157
PMCID:: PMC7069418

See all PubMed Citations (14)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601335.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The beta-globin (HBB) c.93-1G>C variant (also known as IVS-I-130 (G>C)) disrupts a canonical splice-acceptor site and interferes with normal HBB mRNA splicing. In the published literature, the variant is associated with beta(0)-thalassemia (PMIDs: 1517108 (1992), 1577489 (1992), 23510507 (2013), 26182339 (2015), 27828729 (2017)). The frequency of this variant in the general population, 0.000004 (1/251326 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001474478.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The HBB c.93-1G>C variant (rs33943001), also known as IVS-I-130 (G>C), has been reported in individuals with beta-thalassemia trait when identified in a heterozygous state (He 2015, HbVar database and references therein), and beta thalassemia major when found in-trans with a truncating beta globin variant (Asadov 2013). It is listed as pathogenic in ClinVar (Variation ID: 439166), and observed once in the 1000 Genomes Project (1/5008 alleles), and once in the Genome Aggregation Database (1/246102 alleles). The variant is located in the splice consensus sequence, and computational algorithms (Mutation Taster, NNSplice, NetGene2, SpliceSiteFinder-like, MaxEntScan, GeneSplicer, Human Splicing Finder) predict it abolishes the canonical splice acceptor site. Based on the above information, the c.93-1G>C variant is classified as pathogenic. References: Link to HbVar database for IVS-I-130 (G>C): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=831 Asadov C et al. Identification of two rare beta-globin gene mutations in a patient with beta-thalassemia intermedia from Azerbaijan. Hemoglobin. 2013; 37(3):291-6. He S et al. First Detection of a Splice Acceptor Site beta-Thalassemia Mutation: IVS-I-130 (HBB: c.93-1G > C) in a Chinese Patient. Hemoglobin.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV003439603.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

ClinVar contains an entry for this variant (Variation ID: 439166). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is also known as IVS-I-130G>C. Disruption of this splice site has been observed in individuals with autosomal recessive beta thalassemia (PMID: 2283297, 9163586, 28391758, 28670940). This variant is present in population databases (rs33943001, gnomAD 0.003%). This sequence change affects an acceptor 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 29, 2024

ClinVar

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