rs587776828

Positions:

• chr16-172912-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PP5_Moderate

The ENST00000251595.11(HBA2):​c.1del​(p.Met1?) variant causes a frameshift, start lost change. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: HBA2 ENST00000251595.11 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.29

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 60 pathogenic variants in the truncated region.
• PS1: Another start lost variant in ENST00000251595.11 (HBA2) was described as [Likely_pathogenic] in ClinVar as 3075919
• PP5: Variant 16-172912-CA-C is Pathogenic according to our data. Variant chr16-172912-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 15694.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-172912-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.1del	p.Met1?	frameshift_variant, start_lost	1/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.1del	p.Met1?	frameshift_variant, start_lost	1/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000482565.1	n.20del		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.-47del		5_prime_UTR_variant	1/3	2		ENSP00000380908
HBA2	ENST00000484216.1			upstream_gene_variant		1		ENSP00000495899

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

alpha Thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

May 21, 2020

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 30, 2020

The HBA2 c.1delA; p.Met1? variant (rs33950507) is reported in the literature in multiple individuals affected with Hb H disease in trans to the --SEA deletion (Eng 2006, He 2017, Viprakasit 2014). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes a single nucleotide and abolishes the canonical initiation codon of HBA2, so it is predicted to result in an absent protein. Based on available information, this variant is considered to be pathogenic. References: Eng B et al. Three new alpha-thalassemia point mutations ascertained through newborn screening. Hemoglobin. 2006;30(2):149-53. He J et al. Next-generation sequencing improves thalassemia carrier screening among premarital adults in a high prevalence population: the Dai nationality, China. Genet Med. 2017 Sep;19(9):1022-1031. Viprakasit V et al. Clinical presentation and molecular identification of four uncommon alpha globin variants in Thailand. Initiation codon mutation of a2-globin Gene (HBA2:c.1delA), donor splice site mutation of a1-globin gene (IVSI-1, HBA1:c.95 + 1G>A), hemoglobin Queens Park/Chao Pra Ya (HBA1:c.98T>A) and hemoglobin Westmead (HBA2:c.369C>G). Acta Haematol. 2014;131(2):88-94. -

Alpha-thalassemia, Hmong type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2006

- -

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: rs587776828; hg19: chr16-222911;