rs281864867

chr16-173292-A-Cchr16-173292-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000517.6(HBA2):c.263A>C(p.His88Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H88N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 7 uncertain in NM_000517.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.263A>C	p.His88Pro	missense_variant	2/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.263A>C	p.His88Pro	missense_variant	2/3	1	NM_000517.6	P1
HBA2	ENST00000484216.1	c.233A>C	p.His78Pro	missense_variant	2/2	1
HBA2	ENST00000482565.1	n.399A>C		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.167A>C	p.His56Pro	missense_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 12, 2022

The Hb Grifton variant (HBA2: c.263A>C; p.His88Pro, also known as His 87Pro when numbered from the mature protein, rs281864867, HbVar ID: 918) has been reported heterozygous in the literature in individuals described as asymptomatic but with mild to moderate microcytosis (see HbVar and references therein, Waters 2016). In addition, this variant has been associated with erroneously decreased pulse oximetry measurements due to differences in light absorption between oxygenated Hb Grifton variant and oxygenated Hb A (Waters 2016). This variant has been described as unstable and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The histidine at codon 88 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.879). Due to limited information, the clinical significance of the p.His88Pro variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Waters AM et al. Hb Grifton [alpha87(F8)His?Pro; HBA1: C.263A?>?C (or HBA2)] Causes Abnormal Pulse Oximetry Measurements. Hemoglobin. 2016 Aug;40(4):257-9. PMID: 27225845. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Uncertain	23
Dann	Uncertain	0.98
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-9.6	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.82
MutPred		0.97		Gain of methylation at K91 (P = 0.0656);.;
MVP		1.0
MPC		2.9
ClinPred		1.0	D
GERP RS		3.1
gMVP		0.99

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: rs281864867; hg19: chr16-223291;