rs281865555

Positions:

• chr16-172961-A-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]

HBA2 (HGNC:):

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/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.49A>G	p.Lys17Glu	missense_variant	1/3	ENST00000251595.11	NP_000508.1

Ensembl

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

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 13, 2024	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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 21, 2021	- -

HEMOGLOBIN I (TEXAS) Other:1

other, no assertion criteria provided

literature only

OMIM

Mar 28, 2013

- -

HEMOGLOBIN I (SKAMANIA) Other:1

other, no assertion criteria provided

literature only

OMIM

Mar 28, 2013

- -

HEMOGLOBIN I (BURLINGTON) Other:1

other, no assertion criteria provided

literature only

OMIM

Mar 28, 2013

- -

HEMOGLOBIN I Other:1

other, no assertion criteria provided

literature only

OMIM

Mar 28, 2013

- -

HEMOGLOBIN I (PHILADELPHIA) Other:1

other, no assertion criteria provided

literature only

OMIM

Mar 28, 2013

- -

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;