rs63750067

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_StrongBP4BS2_Supporting

The NM_000517.6(HBA2):c.*92A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000383 in 1,542,178 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000039 ( 7 hom. )

Consequence

HBA2
NM_000517.6 3_prime_UTR

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 1.09

Publications

8 publications found

Variant links:

Genes affected

HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]

HBA2 Gene-Disease associations (from GenCC):

alpha thalassemia spectrum
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
erythrocytosis, familial, 7
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
hemoglobin M disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hb Bart's hydrops fetalis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin H disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Heinz body anemia
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
methemoglobinemia, alpha type
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

HBA2 links:

ENSG00000294455 (HGNC:):

ENSG00000294455 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PP5

Variant 16-173692-A-G is Pathogenic according to our data. Variant chr16-173692-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 15647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 7 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.*92A>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11 link	c.*92A>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_000517.6	ENSP00000251595.6		P69905

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

149158

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:

0.000432

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000395

AC:

AN:

1393020

Hom.:

Cov.:

AF XY:

0.0000476

AC XY:

AN XY:

693970

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28192

American (AMR)

AF:

0.0000240

AC:

AN:

41654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25296

East Asian (EAS)

AF:

0.0000260

AC:

AN:

38484

South Asian (SAS)

AF:

0.000296

AC:

AN:

81160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51578

Middle Eastern (MID)

AF:

0.00217

AC:

AN:

5518

European-Non Finnish (NFE)

AF:

0.00000658

AC:

AN:

1063656

Other (OTH)

AF:

0.000174

AC:

AN:

57482

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000268

AC:

AN:

149158

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

72766

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38792

American (AMR)

AF:

0.00

AC:

AN:

15178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000432

AC:

AN:

4630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000776

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

May 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PolyA (A->G) variant (HBA2: c.*92A>G, rs63750067, HbVar ID: 1071), 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(v2.1.1), 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 pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html 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. -

Dec 24, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Also known as Poly A2, poly(A), and poly A signal variant; Located in a regulatory region; in the absence of functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 37644014, 34272389, 1581238, 34426522, 3337900, 29627922, 27199182, 11410420, 7734346, 31286593, 7701914, 1281602, 37745687) -

Aug 10, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

beta Thalassemia

Pathogenic:1

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.*92A>G variant in HBA2, has been reported in multiple families with Hb H disease (both in the homozygous and in the compound heterozygous state (in trans with a double gene deletion) (selected references: Ma 2001 PMID: 11410420, Thein 1988 PMID: 3337900, Yuregir 1992 PMID: 1581238, HbVar database http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1071). This variant has also been reported in ClinVar (Variation ID: 15647). This variant has been identified in 2/68002 European and in 2/4630 South Asian chromosomes by gnomAD. The variant is located in the polyadenylation signal of HBA2, and is predicted to reduce the efficiency of polyadenylation of the globin transcript. Other variants (e.g., c*94A>G) affecting the polyadenylation signal of HBA2 have been reported in individuals with Hb H disease and have been classified as Pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hb H disease. ACMG/AMP Criteria applied: PM3 Very strong, PM2_supporting, PP3). -

alpha Thalassemia

Pathogenic:1

Jan 19, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hemoglobin H disease, nondeletional

Pathogenic:1

Apr 01, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7

Pathogenic:1

Apr 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alpha-thalassemia-2, nondeletional

Pathogenic:1

Apr 01, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hemoglobin H disease

Pathogenic:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

1.1

Mutation Taster

=32/68

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over