dbSNP rs281864819: HBA2:p.Glu24Lys (chr16-172982-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 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. 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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.32

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBA2	ENST00000251595.11 link	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1 link	c.37G>A	p.Glu13Lys	missense_variant	Exon 1 of 2	1		ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1 link	n.89G>A		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA2	ENST00000397806.1 link	c.-2+24G>A		intron_variant	Intron 1 of 2	2		ENSP00000380908.1	G3V1N2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000476

AC:

AN:

420018

Hom.:

Cov.:

AF XY:

0.00000906

AC XY:

AN XY:

220816

show subpopulations

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

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 -

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. -

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

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.21

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

0.0079

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.54

Sift

Uncertain

0.0050

Sift4G

Benign

0.46

Vest4

0.34

MutPred

0.85

Gain of MoRF binding (P = 0.0073);

MVP

1.0

MPC

1.4

ClinPred

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over