rs63751268

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000517.6(HBA2):c.*93_*94delAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.000028 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.19

Publications

1 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: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-173691-TAA-T is Pathogenic according to our data. Variant chr16-173691-TAA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 439772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.93_94delAA		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.93_94delAA		3_prime_UTR_variant	Exon 3 of 3	1	NM_000517.6	ENSP00000251595.6		P69905

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000278

AC:

AN:

1400482

Hom.:

AF XY:

0.0000473

AC XY:

AN XY:

697436

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28416

American (AMR)

AF:

0.00

AC:

AN:

41800

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25366

East Asian (EAS)

AF:

0.00

AC:

AN:

38554

South Asian (SAS)

AF:

0.000430

AC:

AN:

81464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51642

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5536

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1069938

Other (OTH)

AF:

0.0000692

AC:

AN:

57766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

Asia WGS

AF:

0.000942

AC:

AN:

3200

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

alpha Thalassemia

Pathogenic:4

Jan 29, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 21, 2025

MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

The mutation was identified in a patient having HbH diseases -

Mar 17, 2020

Genetics and Molecular Pathology, SA Pathology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PP5, PP1, PM1 -

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The 3 prime UTR variant c.*93_*94del variant in HBA2 gene has been reported previously in multiple individuals affected with microcytic hypochromic anemia / HBA2 related HbH diseasae (Farashi et al., 2015; Deshpande et al., 2015; Prior et al., 2007). This variant is also recognised as alpha2 polyadenylation signal (AATAAA-->AATA- -) in the literature. This variant has been observed to segregate with disease in families (Deshpande et al., 2015). This variant deletes two nucleotides in the 3'UTR in the conserved polyadenylation signal and is predicted to result in an elongated transcript. It has been reported in individuals with Hb H disease in the homozygous state (Deshpande et al., 2015, Farashi et al., 2015, Nair et al., 2013). -

not provided

Pathogenic:2

Jan 28, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBA2 c.*93_*94delAA pathogenic variant is located in the 3'-untranslated region of the HBA2 mRNA and is the deletion of two nucleotides (AA) in the polyadenylation signal sequence. This two nucleotide deletion causes the synthesis of an extended HBA2 mRNA transcript that is nonfunctional (PMID: 7947237 (1994)). This pathogenic variant has been observed in either the homozygous or compound heterozygous state in individuals with mild to severe presentations including Hb H disease and a fatal hydrops fetalis (PMID: 16103716 (2005), 17054428 (2006), and 26193977 (2015)). -

Feb 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBA2 c.*93_*94del variant (rs63751268, HbVar ID: 1072) has been described in the heterozygous state in individuals affected with microcytic hypochromic anemia (Harteveld 1994, HbVar database and references therein). It has been reported in individuals with Hb H disease in the homozygous state (Deshpande 2015, Farashi 2015, Nair 2013) and in the compound heterozygous state with HBA2 Ala130Pro (Deshpande 2015). Furthermore, the c.*93_*94del variant has been reported in the compound heterozygous state with the 3.7kb deletion (Prior 2007) or additional pathogenic variants (Deshpande 2015) in individuals with hematology compatible with alpha thalassemia trait. The c.*93_*94del variant has also been observed to segregate with disease in families (Deshpande 2015, Farashi 2015, Hartveld 1994, Nair 2013, Prior 2007). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes two nucleotides in the 3'UTR in the conserved polyadenylation signal and is predicted to result in an elongated transcript. Several other pathogenic variants in the polyadenylation signal have been reported, and homozygosity of pathogenic variants affecting the HBA2 polyadenylation site has been associated with Hb H disease (Higgs 1983, Thein 1988, Whitelaw 1986). Observations of individuals homozygous for either the c.*93_*94del variant or another variant in the HBA2 polyadenylation signal indicate that these variants may interfere with expression of both HBA2 and HBA1 (Harteveld 1994, Higgs 1983, Thein 1988). Based on available information, the c.*93_*94del variant is considered pathogenic. REFERENCES Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Deshpande P et al. Characterization of Clinical and Laboratory Profiles of the Deletional a2-Globin Gene Polyadenylation Signal Sequence (AATAAA > AATA- -) in an Indian Population. Hemoglobin. 2015;39(6):415-8. PMID: 26365411. Farashi S et al. Homozygosity for the AATAAA > AATA- - Polyadenylation Site Mutation on the a2-Globin Gene Causing Transfusion-Dependent Hb H Disease in an Iranian Patient: A Case Report. Hemoglobin. 2015;39(5):355-8. PMID: 26193977. Harteveld CL et al. A novel polyadenylation signal mutation in the alpha 2-globin gene causing alpha thalassaemia. Br J Haematol. 1994; 87(1):139-43. PMID: 7947237. Higgs D et al. Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature. 1983; 306(5941):398-400. PMID: 6646217. Nair SB et al. Variable presentation of HB H disease due to homozygosity for the rare polyadenylation signal A T(Indian) (AATAAA>AATA- -) mutation in four Indian families. Hemoglobin. 2013;37(3):277-84. PMID: 23517369. Prior JF et al. A moderately severe alpha-thalassemia condition resulting from a combination of the alpha2 polyadenylation signal (AATAAA-->AATA- -) mutation and a 3.7 Kb alpha gene deletion in an Australian family. Hemoglobin. 2007;31(2):173-7. PMID: 17486499. Thein S et al. The polyadenylation site mutation in the alpha-globin gene cluster. Blood. 1988; 71(2):313-9. PMID: 3337900. Whitelaw E et al. Alpha-thalassaemia caused by a poly(A) site mutation reveals that transcriptional termination is linked to 3' end processing in the human alpha 2 globin gene. EMBO J. 1986; 5(11):2915-22. PMID: 3024968. -

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

Pathogenic:1

May 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

Mutation Taster

=16/84

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over