rs63750010

Positions:

chr16-173497-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BS2_Supporting

The NM_000517.6(HBA2):c.326C>A(p.Thr109Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000473 in 1,606,354 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000049 ( 8 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 0.596

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a modified_residue Phosphothreonine (size 0) in uniprot entity HBA_HUMAN

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR,Digenic geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.326C>A	p.Thr109Asn	missense_variant	3/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11 linkuse as main transcript	c.326C>A	p.Thr109Asn	missense_variant	3/3	1	NM_000517.6	ENSP00000251595	P1
	ENST00000702607.1 linkuse as main transcript			downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0000338

AC:

AN:

147818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00108

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000768

AC:

AN:

247506

Hom.:

AF XY:

0.0000893

AC XY:

AN XY:

134342

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:

0.000628

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000487

AC:

AN:

1458424

Hom.:

Cov.:

AF XY:

0.0000744

AC XY:

AN XY:

725324

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:

0.000833

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000338

AC:

AN:

147930

Hom.:

Cov.:

AF XY:

0.0000554

AC XY:

AN XY:

72264

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00107

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	The HBA2 c.326C>A; p.Thr109Asn variant (Hb Bleuland also known as Thr108Asn when numbered from the mature protein, rs63750010, HbVar ID: 2539) is reported in the literature in the heterozygous state in individuals with mild microcytic-hypochromic anemia (Hadavi 2009, Harteveld 2006, Tamaddoni 2009). This variant is also reported in ClinVar (Variation ID: 439114), and is found in the South Asian population with an allele frequency of 0.063% (19/30264 alleles, including a single homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.536). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Hadavi V et al. Alpha-thalassemia mutations in Gilan Province, North Iran. Hemoglobin. 2009;33(3):235-41. PMID: 19657838. Harteveld CL et al. Hb Bleuland (alpha108(G15)Thr-->Asn, ACC-->AAC (alpha2)): a new abnormal hemoglobin associated with a mild alpha-thalassemia phenotype. Hemoglobin. 2006;30(3):349-54. PMID: 16840225. Tamaddoni A et al. alpha-Thalassemia mutation analyses in Mazandaran province, North Iran. Hemoglobin. 2009;33(2):115-23. PMID: 19373587. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 04, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 06, 2017	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 14, 2023

Variant summary: HBA2 c.326C>A (p.Thr109Asn), also referred to as Hb Bleuland, results in a non-conservative amino acid change located in the globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 247506 control chromosomes, predominantly at a frequency of 0.00063 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in HBA2 causing Alpha Thalassemia (7.7e-05 vs 0.0056), allowing no strong conclusion about variant significance. c.326C>A has been reported in the literature in the heterozygous state in at least two individuals affected with mild microcytic-hypochromic anemia (e.g. Harteveld_2006, Hadavi_2009, Tamaddoni_2009). These reports do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. A functional study examining the interaction between the variant and alpha-hemoglobin stabilizing protein found that the variant was recovered with the chaperone at a similar level as the WT protein, suggesting the interaction is normal (Vasseur_2009). However, this study does not address other potential mechanisms that may have an impact on protein stability and/or function and therefore does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 19657838, 16840225, 19373587, 19482015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely pathogenic or uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

.;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.39

M_CAP

Pathogenic

0.60

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Uncertain

0.35

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0080

D;D

Vest4

0.82

MutPred

0.62

Gain of relative solvent accessibility (P = 0.2363);.;

MVP

1.0

MPC

2.6

ClinPred

0.96

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

gMVP

0.89

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