16-172950-C-A

Position:

• chr16-172950-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_Strong BP6

The NM_000517.6(HBA2):​c.38C>A​(p.Ala13Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: not found (cov: 1)
  • Exomes 𝑓: 0.000019 (1 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.164

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 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• BP6: Variant 16-172950-C-A is Benign according to our data. Variant chr16-172950-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 993109.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.38C>A	p.Ala13Asp	missense_variant	Exon 1 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.38C>A	p.Ala13Asp	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6
HBA2	ENST00000484216.1	c.5C>A	p.Ala2Asp	missense_variant	Exon 1 of 2	1		ENSP00000495899.1
HBA2	ENST00000482565.1	n.57C>A		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA2	ENST00000397806	c.-10C>A		5_prime_UTR_variant	Exon 1 of 3	2		ENSP00000380908.1

Frequencies

GnomAD3 genomes Cov.: 1

GnomAD4 exome AF: 0.0000190 AC: 7 AN: 368084 Hom.: 1 Cov.: 0 AF XY: 0.0000310 AC XY: 6 AN XY: 193584

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: 0.000161

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 10, 2024	The Hb-J-Paris-I variant (HBA2: c.38C>A; p.Ala13Asp, also known as Ala12Asp when numbered from the mature protein, rs281864809, HbVar ID: 15) is reported in the literature in individuals with no clinical symptoms or hematological alterations, and is described as a stable hemoglobin variant (see link to HbVar and references therein, de la Fuente-Gonzalo 2019, Kimura 2015, Molchanova 1994). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 13 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.558). Based on available information, this variant is considered to be likely benign. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html de la Fuente-Gonzalo F et al. Characterization of deletional and non-deletional alpha globin variants in a large cohort from Spain between 2009 and 2014. Ann Hematol. 2019 Jul;98(7):1537-1545. PMID: 31025160. Kimura EM et al. Investigating alpha-globin structural variants: a retrospective review of 135,000 Brazilian individuals. Rev Bras Hematol Hemoter. 2015 Mar-Apr;37(2):103-8. PMID: 25818820. Molchanova TP et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994 Oct;88(2):300-6. PMID: 7803274. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 05, 2024	The HBA2 c.38C>A (p.Ala13Asp) variant has been reported in the published literature in individuals with hematological indices and clinical phenotypes within normal range (PMID: 32597250 (2020), 31025160 (2019), 30489691 (2018), 27387985 (2017), 25818820 (2015), and 119167 (1979)). In an online hemoglobin database, this variant is reported as stable (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	18
DANN	Benign	0.91
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.065	N
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.084	T
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.010	D
Sift4G	Benign	0.077	T
Vest4		0.77
MutPred		0.95		Loss of MoRF binding (P = 0.0276);
MVP		1.0
MPC		1.8
ClinPred		0.26	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs281864809; hg19: chr16-222949;