Variant rs63750520 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The ENST00000251595.11(HBA2):c.420del(p.Lys140AsnfsTer9) 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
ENST00000251595.11 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2O:1

Conservation

PhyloP100: 4.21

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 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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. There are 9 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: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.420del	p.Lys140AsnfsTer9	frameshift_variant	3/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HBA2	ENST00000251595.11 linkuse as main transcript	c.420del	p.Lys140AsnfsTer9	frameshift_variant	3/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000482565.1 linkuse as main transcript	n.556del		non_coding_transcript_exon_variant	2/2	1
	ENST00000702607.1 linkuse as main transcript	n.72del		non_coding_transcript_exon_variant	1/1
HBA2	ENST00000397806.1 linkuse as main transcript	c.324del	p.Lys108AsnfsTer9	frameshift_variant	3/3	2		ENSP00000380908

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249094

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134916

show subpopulations

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:

AN:

1459128

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725630

show subpopulations

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.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 20, 2016	- -

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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over