rs281864811

chr16-172958-G-Achr16-172958-G-Cchr16-172958-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5

The NM_000517.6(HBA2):c.46G>A(p.Gly16Ser) 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. G16C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 2)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.396

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 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-172958-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1683493.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.46G>A	p.Gly16Ser	missense_variant	1/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.46G>A	p.Gly16Ser	missense_variant	1/3	1	NM_000517.6	P1
HBA2	ENST00000484216.1	c.16G>A	p.Gly6Ser	missense_variant	1/2	1
HBA2	ENST00000482565.1	n.65G>A		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.-2G>A		splice_region_variant, 5_prime_UTR_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 2

GnomAD3 exomes AF: 0.0000187 AC: 1 AN: 53380 Hom.: 0 AF XY: 0.0000372 AC XY: 1 AN XY: 26900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000127

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000283 AC: 11 AN: 388200 Hom.: 0 Cov.: 0 AF XY: 0.0000245 AC XY: 5 AN XY: 204132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000424

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 2

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

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

May 09, 2023

Variant summary: HBA2 c.46G>A (p.Gly16Ser) results in a non-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 allele was found at a frequency of 1.9e-05 in 53380 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.46G>A has been reported in the literature as a non-informative heterozygous genotype in a proband who had a clinical diagnosis of beta-thalassemia attributed to two different compound heterozygous HBB gene variants, namely IVS-II-654C>T and the Southeast Asian (SEA) typehereditary persistence of fetal hemoglobin (SEA-HPFH) variant (Wu_2017). It has also been reported as a non-informative genotype in settings of alpha-thalassemia carrier testing and as an incidental variant in settings of HbA1c measurements (example, Xu_2021, Wu_2017). These report(s) 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: 28901454, 34309461, 31286593, 30809867). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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	Benign	-0.10	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	16
Dann	Benign	0.84
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.21	N
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.050	N
REVEL	Uncertain	0.41
Sift	Benign	0.28	T
Sift4G	Benign	0.44	T
Vest4		0.70
MutPred		0.58		Gain of glycosylation at G16 (P = 0.0403);
MVP		0.99
MPC		1.3
ClinPred		0.029	T
GERP RS		-0.90
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs281864811; hg19: chr16-222957;