rs63750520

Positions:

• chr16-173588-CA-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_000517.6(HBA2):​c.420delA​(p.Lys140fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000343 in 1,459,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HBA2 NM_000517.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: 4.21

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.021 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-173588-CA-C is Pathogenic according to our data. Variant chr16-173588-CA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15629.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.420delA	p.Lys140fs	frameshift_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.420delA	p.Lys140fs	frameshift_variant	3/3	1	NM_000517.6	ENSP00000251595.6
HBA2	ENST00000482565.1	n.556delA		non_coding_transcript_exon_variant	2/2	1
HBA2	ENST00000397806.1	c.324delA	p.Lys108fs	frameshift_variant	3/3	2		ENSP00000380908.1
ENSG00000290038	ENST00000702607.1	n.72delT		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249094 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459128 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 725630

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 20, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	The HBA2 c.420del; p.Lys140AsnfsTer9 variant (Hb Wayne, also known as Lys139fs when numbered from the mature protein; rs63750520; HbVar ID: 702) has been reported in individuals with no clinical abnormalities (Salkie 1992, Seid-Akhavan 1976, HbVar database); however, its phenotype in the presence of other pathogenic globin variants is uncertain. The variant hemoglobin comprises 4-6% (Seid-Akhavan 1976) or 12-16% of total hemoglobin (Huisman 1984), depending on the purification methodology. Functional characterization of the variant hemoglobin indicates increased oxygen affinity and strong reduction in Bohr effect (Huisman 1984). The variant is listed in ClinVar (Variation ID: 15629) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The variant causes a frameshift that replaces the last three amino acids with eight novel amino acids at the C terminus. Although the variant causes protein translation past the canonical termination codon, it is not predicted to impact the downstream polyadenylation site (PolyA signal miner). Due to the limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Huisman T et al. Hb Wayne, the frameshift variant with extended alpha chains observed in a Caucasian family from Alabama. Hemoglobin. 1984; 8(1):1-15. PMID: 6327575. Salkie M et al. A Canadian family with Hb Wayne; characterization by HPLC and DNA sequencing. Hemoglobin. 1992; 16(6):515-9. PMID: 1487423. Seid-Akhavan M et al. Hemoglobin Wayne: a frameshift mutation detected in human hemoglobin alpha chains. Proc Natl Acad Sci U S A. 1976; 73(3):882-6. PMID: 1062801. -

alpha Thalassemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 09, 2021

- -

HEMOGLOBIN WAYNE Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 12, 2022

- -

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: rs63750520; hg19: chr16-223587;