NM_000517.6(HBA2):c.*92A>G AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 10, 2023
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:: RCV000507591.21

Allele description [Variation Report for NM_000517.6(HBA2):c.*92A>G]

NM_000517.6(HBA2):c.*92A>G

Genes:

LOC106804612:hemoglobin subunit alpha 2 recombination region [Gene]
HBA2:hemoglobin subunit alpha 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000517.6(HBA2):c.*92A>G

HGVS:

NC_000016.10:g.173692A>G
NG_000006.1:g.34555A>G
NG_046165.1:g.3431A>G
NG_059186.1:g.2042A>G
NG_059271.1:g.5846A>G
NM_000517.6:c.*92A>GMANE SELECT
LRG_1240t1:c.*92A>G
LRG_1225:g.2042A>G
LRG_1240:g.5846A>G
NC_000016.9:g.223691A>G
NM_000517.4:c.*92A>G

Nucleotide change:

3-UNT, A-G, +4

Links:

OMIM: 141850.0024; dbSNP: rs63750067

NCBI 1000 Genomes Browser:

rs63750067

Molecular consequence:

NM_000517.6:c.*92A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000601205	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Aug 10, 2023)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 7701914, 1281602, 1581238, 7734346, 11410420, 34272389, 34426522, 29627922, 31286593, 26467025
SCV000603882	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Jun 30, 2023)	germline	clinical testing	Citation Link,
SCV002575801	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 23, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000601205

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Aug 10, 2023)

unknown

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV000603882

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Pathogenic
(Jun 30, 2023)

germline

clinical testing

Citation Link,

SCV002575801

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 23, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Molecular characterization of alpha-thalassemia determinants, beta-thalassemia alleles, and beta S haplotypes among Kuwaiti Arabs.

Adekile AD, Gu LH, Baysal E, Haider MZ, al-Fuzae L, Aboobacker KC, al-Rashied A, Huisman TH.

Acta Haematol. 1994;92(4):176-81.

PubMed [citation]

PMID:: 7701914

Hb H disease caused by a homozygosity for the AATAAA-->AATAAG mutation in the polyadenylation site of the alpha 2-globin gene: hematological observations.

Fei YJ, Oner R, Bözkurt G, Gu LH, Altay C, Gurgey A, Fattoum S, Baysal E, Huisman TH.

Acta Haematol. 1992;88(2-3):82-5.

PubMed [citation]

PMID:: 1281602

See all PubMed Citations (10)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601205.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This pathogenic variant changes the polyadenylation signal of the alpha2-globin gene from AATAAA to AATGAA and is associated with alpha-thalassemia. In the published literature, this variant has been reported in individuals with alpha thalassemia (PMID: 29627922 (2018)) and Hb H disease as homozygous and compound heterozygous with other pathogenic alpha-globin variants (PMIDs: 11410420 (2001), 7734346 (1995), 7701914 (1994), 1581238 (1992), 1281602 (1992)). Functional studies report this variant results nonfunctional and unstable mRNA (PMIDs: 1581238 (1992), 1281602 (1992)). Based on the available information, the 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, SCV000603882.6

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

Description

The PolyA (A->G) variant (HBA2: c.*92A>G, rs63750067), has been reported in multiple families with Hb H disease when homozygous or in-trans with a double gene deletion (Ma 2001, Thein 1988, Yuregir 1992, HbVar database and references therein). This variant is also reported in ClinVar (Variation ID: 15647). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The variant is located in the polyadenylation signal of HBA2, and is predicted to reduce the efficiency of polyadenylation of the globin transcript. Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database for PolyA (A->G): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1071 Ma ES et al. Interaction between (--SEA) alpha-thalassemia deletion and uncommon non-deletional alpha-globin gene mutations in Chinese patients. Haematologica. 2001 May;86(5):539-40. PMID: 11410420. Thein SL et al. The polyadenylation site mutation in the alpha-globin gene cluster. Blood. 1988 Feb;71(2):313-9. PMID: 3337900. Yuregir G et al. Hb H disease in a Turkish family resulting from the interaction of a deletional alpha-thalassaemia-1 and a newly discovered poly A mutation. Br J Haematol. 1992; 80(4):527-32. PMID: 1581238.

#	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 GeneDx, SCV002575801.3

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

Description

Also known as Poly A2, poly(A), and poly A signal variant; This variant is associated with the following publications: (PMID: 34272389, 1581238, 34426522, 3337900, 29627922, 27199182, 11410420, 7734346, 31286593, 7701914, 1281602)

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

Last Updated: Oct 26, 2024

ClinVar

Relating variation to medicine