16-173253-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000517.6(HBA2):c.224A>G(p.Asp75Gly) 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D75A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.224A>G	p.Asp75Gly	missense_variant	2/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.224A>G	p.Asp75Gly	missense_variant	2/3	1	NM_000517.6	P1
HBA2	ENST00000484216.1	c.194A>G	p.Asp65Gly	missense_variant	2/2	1
HBA2	ENST00000482565.1	n.360A>G		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.128A>G	p.Asp43Gly	missense_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 27, 2018

The HBA2 c.224A>G; Asp74Gly variant, also known as Hb Chapel Hill, is reported in the literature as an unstable variant with slightly increased oxygen affinity, and has been found in the heterozygous state in individuals with both mild, persistent erythrocytosis and mild anemia (see link to HbVar and references therein). Additionally, the phenotype of this variant in the presence of other alpha globin variants is unknown. This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), but is in a low coverage region. The aspartic acid at codon 74 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, although these are low confidence predictions. Due to conflicting information, the clinical significance of the Hb Chapel Hill variant is uncertain at this time, but could possibly result in autosomal dominant mild erythrocytosis. References: Link to HbVar for Hb Chapel Hill: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=110 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0070	D;D
Vest4		0.74
MutPred		0.96		Loss of disorder (P = 0.1328);.;
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		4.2
gMVP		0.93

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: rs281864856; hg19: chr16-223252;