rs63750678

Variant names:

• chr16-172913-AT-A
• rs63750678
• NM_000517.6:c.2delT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_000517.6(HBA2):​c.2delT​(p.Met1ArgfsTer49) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: HBA2 NM_000517.6 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.03
• Publications: 0 publications found

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

ENSG00000294455 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 81 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_000517.6 (HBA2) was described as [Pathogenic] in ClinVar as 15645
• PP5: Variant 16-172913-AT-A is Pathogenic according to our data. Variant chr16-172913-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 15692.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	c.2delT	p.Met1ArgfsTer49	frameshift_variant, start_lost	Exon 1 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.2delT	p.Met1ArgfsTer49	frameshift_variant, start_lost	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000744 AC: 2 AN: 268920 Hom.: 0 Cov.: 0 AF XY: 0.00000698 AC XY: 1 AN XY: 143308

African (AFR) AF: 0.00 AC: 0 AN: 6640

American (AMR) AF: 0.00 AC: 0 AN: 13128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7414

East Asian (EAS) AF: 0.000136 AC: 2 AN: 14680

South Asian (SAS) AF: 0.00 AC: 0 AN: 42036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1018

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 155676

Other (OTH) AF: 0.00 AC: 0 AN: 14226

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 10, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBA2 c.2del variant disrupts the translation initiation codon of the HBA2 mRNA and is predicted to interfere with HBA2 protein synthesis. This variant has been reported in individuals with Hb H disease (PMID: 9322079 (1997), Quest internal data). This variant has also been observed in individuals undergoing thalassemia screening (PMID: 34293487 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Sep 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBA2 c.2del; p.Met1? variant (also known as initiation codon (-T), rs63750678, HbVar ID: 1062), is reported in the literature in individuals affected with HbH disease who also carried a large deletion encompassing both the HBA1 and HBA2 genes on the other chromosome (see link to HbVar and references therein; Viprakasit 2005). This variant is reported in ClinVar (Variation ID: 15692), and abolishes the canonical initiation codon of HBA2, so it is predicted to result in an absent protein. Other variants that disrupt the initiation codon have been reported in individuals with alpha thalassemias and are considered pathogenic (Eng 2006, Olivieri 1987). Based on available information, the c.2del; p.Met1? variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Eng B et al. Three new alpha-thalassemia point mutations ascertained through newborn screening. Hemoglobin. 2006;30(2):149-53. PMID: 16798638. Olivieri NF et al. An alpha-globin gene initiation codon mutation in a black family with HbH disease. Blood. 1987 Sep;70(3):729-32. PMID: 3620699. Viprakasit V et al. A rare association of alphaO-thalassemia (--SEA) and an initiation codon mutation (ATG-->A-G) of the alpha2 gene causes Hb H disease in Thailand. Hemoglobin. 2005;29(3):235-40. PMID: 16116675. -

alpha Thalassemia Pathogenic:1

Aug 31, 2018

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hemoglobin H disease, nondeletional Pathogenic:1

Jan 01, 2005

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

Mar 29, 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		2.0
Mutation Taster		=17/183	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs63750678; hg19: chr16-222912;