rs281865555

Variant names:

• chr16-172961-A-G
• rs281865555
• NM_000517.6:c.49A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_Strong BP6

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K17M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 2)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:5
• Conservation: PhyloP100: 4.35

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• 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 id is 15635.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.49A>G	p.Lys17Glu	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6
HBA2	ENST00000484216.1	c.16A>G	p.Lys6Glu	missense_variant	Exon 1 of 2	1		ENSP00000495899.1
HBA2	ENST00000482565.1	n.68A>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA2	ENST00000397806.1	c.-2+3A>G		splice_region_variant, intron_variant	Intron 1 of 2	2		ENSP00000380908.1

Frequencies

GnomAD3 genomes Cov.: 2

GnomAD4 exome AF: 0.0000130 AC: 5 AN: 384714 Hom.: 0 Cov.: 0 AF XY: 0.00000988 AC XY: 2 AN XY: 202358

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: 0.0000218

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign: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
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	22
DANN	Benign	0.51
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.82
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.26	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Vest4		0.83
MutPred		0.88		Loss of MoRF binding (P = 0.0034);
MVP		1.0
MPC		1.8
ClinPred		0.92	D
GERP RS		1.4
gMVP		0.88

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: rs281865555; hg19: chr16-222960;