rs281865555

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PP3_StrongBP6

The NM_000517.6(HBA2):c.49A>G(p.Lys17Glu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 2)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1O:5

Conservation

PhyloP100: 4.35

Publications

1 publications found

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 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

HBA2 links:

ENSG00000294455 (HGNC:):

ENSG00000294455 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 11 uncertain in NM_000517.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

BP6

Variant 16-172961-A-G is Benign according to our data. Variant chr16-172961-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15635.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.49A>G	p.Lys17Glu	missense_variant	Exon 1 of 3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11 link	c.49A>G	p.Lys17Glu	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6		P69905

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000130

AC:

AN:

384714

Hom.:

Cov.:

AF XY:

0.00000988

AC XY:

AN XY:

202358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9274

American (AMR)

AF:

0.00

AC:

AN:

16806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11812

East Asian (EAS)

AF:

0.00

AC:

AN:

25696

South Asian (SAS)

AF:

0.00

AC:

AN:

43504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1642

European-Non Finnish (NFE)

AF:

0.0000218

AC:

AN:

229640

Other (OTH)

AF:

0.00

AC:

AN:

21914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1Other:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Sep 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Hb I variant (HBA2: c.49A>G; p.Lys17Glu, also known as Lys16Glu when numbered from the mature protein, rs281865555, HbVar ID: 19) is reported in the literature in an individual who also carried an alpha globin deletion (Liebhaber 1984), but it has not been associated with any clinically significant phenotypes (HbVar database and references therein). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The lysine at codon 17 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.614). Based on available information, the Hb I variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Liebhaber S et al. Hemoglobin I mutation encoded at both alpha-globin loci on the same chromosome: concerted evolution in the human genome. Science. 1984; 226(4681):1449-51. -

Feb 13, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBA2 c.49A>G (p.Lys17Glu) variant (also known as Hb I) has been described to have normal stability. Individuals who are heterozygous for this variant have a normal clinical presentation (see HbVar (http://globin.bx.psu.edu/hbvar/, and PMIDs: 7803274 (1994), 6085353 (1984), 740406 (1978), 5480848 (1970)). One individual carrying Hb I in both alpha-1 and alpha-2 genes on the same chromosome was also clinically healthy (PMID: 6505702 (1984)). Based on the available information, we are unable to determine the clinical significance of this variant. -

HEMOGLOBIN I (TEXAS)

Other:1

Mar 28, 2013

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

HEMOGLOBIN I (SKAMANIA)

Other:1

Mar 28, 2013

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

HEMOGLOBIN I (BURLINGTON)

Other:1

Mar 28, 2013

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

HEMOGLOBIN I

Other:1

Mar 28, 2013

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

HEMOGLOBIN I (PHILADELPHIA)

Other:1

Mar 28, 2013

OMIM

Significance:other

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

(source)

DANN

Benign

0.51

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.82

FATHMM_MKL

Uncertain

0.87

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.26

PhyloP100

4.3

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Vest4

0.83

MutPred

0.88

Loss of MoRF binding (P = 0.0034);

MVP

1.0

MPC

1.8

ClinPred

0.92

GERP RS

1.4

PromoterAI

-0.095

Neutral

(source)

gMVP

0.88

Mutation Taster

=37/63

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over