rs63751268

Positions:

• chr16-173691-TAA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_000517.6(HBA2):​c.*93_*94del 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.19

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 16-173691-TAA-T is Pathogenic according to our data. Variant chr16-173691-TAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.*93_*94del		3_prime_UTR_variant	3/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.*93_*94del		3_prime_UTR_variant	3/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000397806.1	c.*93_*94del		3_prime_UTR_variant	3/3	2		ENSP00000380908
	ENST00000702607.1			upstream_gene_variant
HBA2	ENST00000482565.1			downstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000278 AC: 39 AN: 1400482 Hom.: 2 AF XY: 0.0000473 AC XY: 33 AN XY: 697436

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000430

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000692

GnomAD4 genome Cov.: 25

Bravo AF: 0.00000756

Asia WGS AF: 0.000942 AC: 3 AN: 3200

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

alpha Thalassemia Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Mar 17, 2020	PM2, PP5, PP1, PM1 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 22, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 28, 2020	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)). -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs63751268; hg19: chr16-223690;