rs281865555

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_StrongBP6

The NM_000517.6(HBA2):ā€‹c.49A>Gā€‹(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 š‘“: 0.000013 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

6
5
4

Clinical Significance

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

Conservation

PhyloP100: 4.35
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 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
HBA2NM_000517.6 linkuse as main transcriptc.49A>G p.Lys17Glu missense_variant 1/3 ENST00000251595.11 NP_000508.1 P69905D1MGQ2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HBA2ENST00000251595.11 linkuse as main transcriptc.49A>G p.Lys17Glu missense_variant 1/31 NM_000517.6 ENSP00000251595.6 P69905
HBA2ENST00000484216.1 linkuse as main transcriptc.16A>G p.Lys6Glu missense_variant 1/21 ENSP00000495899.1 A0A2R8Y7C0
HBA2ENST00000482565.1 linkuse as main transcriptn.68A>G non_coding_transcript_exon_variant 1/21
HBA2ENST00000397806.1 linkuse as main transcriptc.-2+3A>G splice_region_variant, intron_variant 2 ENSP00000380908.1 G3V1N2

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
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:
0.0000218
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
2

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
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesDec 21, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJan 17, 2023The HBA2 c.49A>G (p.Lys17Glu or Lys16Glu) variant, also known as Hb I, is reported as having normal function and stability. Individuals heterozygous for this variant have normal clinical presentations with Hb I being 15-28% of the total hemoglobin (PMID: 7803274 (1994), 6085353 (1984)). Based on the available information, we are unable to determine the clinical significance of this variant. -
HEMOGLOBIN I (TEXAS) Other:1
other, no assertion criteria providedliterature onlyOMIMMar 28, 2013- -
HEMOGLOBIN I (SKAMANIA) Other:1
other, no assertion criteria providedliterature onlyOMIMMar 28, 2013- -
HEMOGLOBIN I (BURLINGTON) Other:1
other, no assertion criteria providedliterature onlyOMIMMar 28, 2013- -
HEMOGLOBIN I Other:1
other, no assertion criteria providedliterature onlyOMIMMar 28, 2013- -
HEMOGLOBIN I (PHILADELPHIA) Other:1
other, no assertion criteria providedliterature onlyOMIMMar 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs281865555; hg19: chr16-222960; API