rs281864858

Positions:

• chr16-173255-G-A
• chr16-173255-G-C
• chr16-173255-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000517.6(HBA2):​c.226G>A​(p.Asp76Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D76A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.771

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-173255-G-A is Benign according to our data. Variant chr16-173255-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 619849.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.226G>A	p.Asp76Asn	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.226G>A	p.Asp76Asn	missense_variant	2/3	1	NM_000517.6	ENSP00000251595.6
HBA2	ENST00000484216.1	c.193G>A	p.Asp65Asn	missense_variant	2/2	1		ENSP00000495899.1
HBA2	ENST00000482565.1	n.362G>A		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.130G>A	p.Asp44Asn	missense_variant	2/3	2		ENSP00000380908.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 04, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 23, 2024

Variant summary: HBA2 c.226G>A (p.Asp76Asn) results in a conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 139942 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.226G>A has been reported in the literature as heterozygous in individuals without apparent Autosomal recessive Alpha Thalassemia (Yi-Tao_1982, Eftekhari_2018, Perutz_1990). These reports do not provide unequivocal conclusions about association of the variant with Alpha Thalassemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29651217, 2285785, 6814490). ClinVar contains an entry for this variant (Variation ID: 619849). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.031	.;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.51	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	-0.0028	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.39
Sift	Benign	0.031	D;D
Sift4G	Benign	0.48	T;T
Vest4		0.39
MutPred		0.70		Loss of disorder (P = 0.1834);.;
MVP		0.99
MPC		1.3
ClinPred		0.54	D
GERP RS		3.2
gMVP		0.78

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: rs281864858; hg19: chr16-223254;