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rs63750520

chr16-173588-CA-C

Variant summary

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

The NM_000517.6(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
NM_000517.6 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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
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
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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 UniProt
HBA2NM_000517.6 linkuse as main transcriptc.420del p.Lys140AsnfsTer9 frameshift_variant 3/3 ENST00000251595.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBA2ENST00000251595.11 linkuse as main transcriptc.420del p.Lys140AsnfsTer9 frameshift_variant 3/31 NM_000517.6 P1
HBA2ENST00000482565.1 linkuse as main transcriptn.556del non_coding_transcript_exon_variant 2/21
ENST00000702607.1 linkuse as main transcriptn.72del non_coding_transcript_exon_variant 1/1
HBA2ENST00000397806.1 linkuse as main transcriptc.324del p.Lys108AsnfsTer9 frameshift_variant 3/32

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
26
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249094
Hom.:
0
AF XY:
0.00000741
AC XY:
1
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:
5
AN:
1459128
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
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
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
26
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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 01, 2023The 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 submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoDec 20, 2016- -
alpha Thalassemia Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Feb 09, 2021- -
HEMOGLOBIN WAYNE Other:1
other, no assertion criteria providedliterature onlyOMIMSep 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.

Other links and lift over

dbSNP: rs63750520; hg19: chr16-223587; API