rs281864874

Variant names:

• chr16-173304-T-C
• rs281864874
• NM_000517.6:c.275T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000517.6(HBA2):​c.275T>C​(p.Leu92Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (★). 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. L92F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.32

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 16-173304-T-C is Pathogenic according to our data. Variant chr16-173304-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3766787.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.275T>C	p.Leu92Pro	missense_variant	Exon 2 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.275T>C	p.Leu92Pro	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Port Phillip variant (HBA2: c.275T>C; p.Leu92Pro, also known as Leu91Pro when numbered from the mature protein, rs281864874, HbVar ID: 145) has been reported in heterozygous individuals with moderately reduced oxygen saturation and mild anemia (Brennan 1977, Du 2021), and has been reported as compound heterozygotes in individuals with severe anemia (Chen 2024, Du 2021). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.865). Additionally, other variants at this codon (c.275T>A, p.Leu92His; c.274C>A, p.Leu92Ile; c.274C>T, p.Leu92Phe) have been reported in individuals with moderately reduced oxygen affinity with unremarkable RBC indices (Barberio 2013, Kelany 2016, Pasquarella 2022). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Barberio G et al. Hb Treviso [a91(FG3)Leu?Phe (a2)]: a new slightly unstable hemoglobin variant with moderately decreased oxygen affinity. Hemoglobin. 2013 PMID: 23350769. Brennan SO et al. Haemoglobin Port Phillip alpha91 (FG3) Leu replaced by Pro, a new unstable haemoglobin. FEBS letters. 1977 Sep 1. PMID: 902765. Chen YP et al. Identification of Novel Hb Guiyang [HBA2: c.151C > A a2 50 (CE8) His- Asn] and Phenotype- Genotype Correlation of Abnormal Hemoglobins in Guizhou, Southwest China. J Blood Med. 2024 PMID: 38895162. Du L et al. Compounded with hemoglobin Port Phillip and -a(4.2) or --(SEA) deletions were identified in Chinese population. Mol Genet Genomic Med. 2021 Sep. PMID: 34398528. Kelany M et al. Hb Kalavasos [HBA2: c.275T?>?A; p.Leu92His]: a Novel a Chain Hemoglobin Variant. Hemoglobin. 2016 Sep. PMID: 27624082. Pasquarella A et al. Hemoglobin Alpha Chain Variant Zara Associated With Familial Asymptomatic Hypoxemia. J Hematol. 2022 Oct. PMID: 36406831. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.95
MutPred		0.28		Loss of stability (P = 0.0028);.;
MVP		1.0
MPC		3.2
ClinPred		1.0	D
GERP RS		4.2
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: rs281864874; hg19: chr16-223303;