rs281864819

Positions:

• chr16-172982-G-A
• chr16-172982-G-C
• chr16-172982-G-T

Variant summary

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

The NM_000517.6(HBA2):​c.70G>A​(p.Glu24Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. E24G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 2)
  • Exomes 𝑓: 0.0000048 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.70G>A	p.Glu24Lys	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.70G>A	p.Glu24Lys	missense_variant	1/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000484216.1	c.40G>A	p.Glu14Lys	missense_variant	1/2	1		ENSP00000495899
HBA2	ENST00000482565.1	n.89G>A		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.-2+24G>A		intron_variant		2		ENSP00000380908

Frequencies

GnomAD3 genomes Cov.: 2

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000476 AC: 2 AN: 420018 Hom.: 1 Cov.: 0 AF XY: 0.00000906 AC XY: 2 AN XY: 220816

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: 0.0000449

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 05, 2023	The Hb Chad variant (HBA2: c.70G>A; p.Glu24Lys, also known as Glu23Lys when numbered from the mature protein, rs281864819) is reported in the literature in individuals with hypochromia or no clinical symptoms, and does not contribute to the clinical phenotype when found with other structural variants (see link to HbVar database for Hb Chad and references therein). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.535). Additionally, other variants at this codon (Hb Memphis, Hb G-Audhali, Hb Dayton, Hb Reims, Hb Lisbon) have been reported in individuals with no clinical symptoms (see link to HbVar database and references therein). While the available information suggests that this is a benign structural variant, due to the presence of individuals with hypochromia, the clinical significance of the Hb Chad variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 31, 2023	In the published literature, this variant has been reported in individuals and families examined for hemoglobin variation in Chad (PMID: 5714528 (1968)), China (PMID: 4786652 (1973)), Japan (PMID: 6689417 (1983)), and Suriname (PMID: 2606723 (1989)). Some individuals heterozygous for this variant have normal clinical presentations while others presented with microcytosis and hypochromia (PMID: 2606723 (1989)), as well as polycythemia (PMID: 6689417 (1983)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

alpha Thalassemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.21	N
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.0079	D
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.46	T
Vest4		0.34
MutPred		0.85		Gain of MoRF binding (P = 0.0073);
MVP		1.0
MPC		1.4
ClinPred		0.45	T
GERP RS		3.0
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs281864819; hg19: chr16-222981;