rs281864863

Positions:

• chr16-173271-T-G

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.242T>G​(p.Leu81Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,364,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.40

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 (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, 0.995
• PP5: Variant 16-173271-T-G is Pathogenic according to our data. Variant chr16-173271-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 993412.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.242T>G	p.Leu81Arg	missense_variant	2/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.242T>G	p.Leu81Arg	missense_variant	2/3	1	NM_000517.6	ENSP00000251595.6
HBA2	ENST00000484216.1	c.209T>G	p.Leu70Arg	missense_variant	2/2	1		ENSP00000495899.1
HBA2	ENST00000482565.1	n.378T>G		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.146T>G	p.Leu49Arg	missense_variant	2/3	2		ENSP00000380908.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1364622 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 677298

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.42e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 16, 2019

The Hb Ann Arbor variant (HBA2: c.242T>G; p.Leu81Arg, also known as Leu80Arg when numbered from the mature protein rs281864863) is reported in the literature in two brothers affected with hemolytic microcytic anemia (Adams 1972, Adams 1974, HbVar database). Both affected brothers carried Hb Ann Arbor in the heterozygous state and were presumed to carry an additional undetermined alpha-thalassemia allele in trans, although this second allele was not determined (Adams 1974). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The affected brothers with Hb Ann Arbor exhibited 10-15% abnormal hemoglobin, while other family members that carried Hb Ann Arbor exhibited 2-5% abnormal hemoglobin (Adams 1974). The proportions of abnormal hemoglobin in heterozygous carriers, heat stability assays, and functional assays of protein synthesis all suggest Hb Ann Arbor is unstable and rapidly degraded (Adams 1972, Adams 1974). Based on available information, this variant is considered to be likely pathogenic. References: Link to Hb Ann Arbor in HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=123 Adams JG 3rd et al. Biosynthesis of hemoglobin Ann Arbor: evidence for catabolic and feedback regulation. Science. 1972 Jun 30;176(4042):1427-9. Adams JG 3rd. Hemoglobin Ann Arbor: disturbance in the coordinated biosynthesis of globin chains? Ann N Y Acad Sci. 1974 Nov 29;241(0):232-41. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.95
MutPred		0.91		Gain of methylation at L81 (P = 0.0199);.;
MVP		1.0
MPC		3.0
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: rs281864863; hg19: chr16-223270;