rs267607269

Variant names:

• chr16-173515-C-G
• rs267607269
• NM_000517.6:c.344C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-173515-C-G
• chr16-173515-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000517.6(HBA2):​c.344C>G​(p.Pro115Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P115L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 25)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.262

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]

ENSG00000290038 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.344C>G	p.Pro115Arg	missense_variant	Exon 3 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.344C>G	p.Pro115Arg	missense_variant	Exon 3 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 25

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

HBA2-related disorder Uncertain:1

Feb 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HBA2 c.344C>G variant is predicted to result in the amino acid substitution p.Pro115Arg. This variant is also known as Hb Chiapas or p.Pro114Arg using legacy nomenclature. Individuals carrying this variant were described as clinically normal (Lisker et al. 1966. PubMed ID: 5945763; Jones et al. 1968. PubMed ID: 5650416; Ibarra et al. 1981. PubMed ID: 7319830). This variant has not been reported in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Mar 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Chiapas (HBA2: c.344C>G; p.Pro115Arg, also known as Pro114Arg when numbered from the mature protein, rs267607269, HbVar ID:176) is reported in the literature in an heterozygous individual during surveys with no known associated clinical symptoms (Jones 1968, Ibarra 1981, HbVar and references therein). This variant is not reported in ClinVar and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Although the resulting Hb product was readily identifiable by electrophoresis and was tested as normal stability (Ibarra 1981), there is no other functional and structural outcome known. The phenotype of this variant in the presence of other alpha globin variants is unknown either. The proline at codon 115 is moderately conserved, but computational are uncertain whether this variant is neutral or deleterious (REVEL: 0.468). Due to limited information, the clinical significance of the Hb Chiapas variant is uncertain at this time. References: Jones, R. T., et al. Chemical characterization of hemoglobinMexico and hemoglobinChiapas. Biochimica et Biophysica Acta (BBA). Protein Structure 1968; 154(3): 488-495. Ibarra B et al. Hb Chiapas alpha 2 114 Pro replaced by Arg beta 2: identification by high pressure liquid chromatography. Hemoglobin. 1981;5(6):605-8. PMID: 7319830. Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.14	.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.18	N
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	0.25	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.070	T;T
Vest4		0.25
MutPred		0.55		Loss of phosphorylation at T119 (P = 0.1732);.;
MVP		0.98
MPC		1.4
ClinPred		0.75	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.90

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: rs267607269; hg19: chr16-223514;