rs63750067

Positions:

chr16-173692-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The ENST00000251595.11(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
ENST00000251595.11 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.09

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PP5

Variant 16-173692-A-G is Pathogenic according to our data. Variant chr16-173692-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.*92A>G		3_prime_UTR_variant	3/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris
HBA2	ENST00000251595.11 linkuse as main transcript	c.*92A>G	3_prime_UTR_variant	3/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000397806.1 linkuse as main transcript	c.*92A>G	3_prime_UTR_variant	3/3	2		ENSP00000380908
	ENST00000702607.1 linkuse as main transcript		upstream_gene_variant
HBA2	ENST00000482565.1 linkuse as main transcript		downstream_gene_variant		1

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000240

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000260

Gnomad4 SAS exome

AF:

0.000296

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000658

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.0000268

AC:

AN:

149158

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

72766

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000432

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

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

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 10, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 30, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2023	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) -

alpha Thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 19, 2021

- -

beta Thalassemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2022

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). -

Hemoglobin H disease, nondeletional

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1992

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 15, 2022

- -

Alpha-thalassemia-2, nondeletional

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1992

- -

Hemoglobin H disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.67

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

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