rs281864819

Variant names:

• chr16-172982-G-A
• rs281864819
• NM_000517.6:c.70G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

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. E24A) has been classified as Uncertain significance.

• 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
• Publications: 0 publications found

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]

HBA2 Gene-Disease associations (from GenCC):

• alpha thalassemia spectrum

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hemoglobin M disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hb Bart's hydrops fetalis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin H disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Heinz body anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000294455 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 13 uncertain in NM_000517.6

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6

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

African (AFR) AF: 0.00 AC: 0 AN: 10260

American (AMR) AF: 0.00 AC: 0 AN: 18124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12948

East Asian (EAS) AF: 0.00 AC: 0 AN: 28726

South Asian (SAS) AF: 0.0000449 AC: 2 AN: 44522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1806

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 252102

Other (OTH) AF: 0.00 AC: 0 AN: 24060

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

May 31, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 05, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

alpha Thalassemia Uncertain:1

May 21, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
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
PhyloP100		2.3
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
PromoterAI		-0.0064	Neutral
gMVP		0.75
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs281864819; hg19: chr16-222981;