rs41321052

chr16-173478-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PP3_Strong BP6

The NM_000517.6(HBA2):c.307A>C(p.Ser103Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,060 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.811

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000517.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• BP6: Variant 16-173478-A-C is Benign according to our data. Variant chr16-173478-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1330535.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.307A>C	p.Ser103Arg	missense_variant	3/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.307A>C	p.Ser103Arg	missense_variant	3/3	1	NM_000517.6	P1
	ENST00000702607.1			downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248256 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458060 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725166

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 01, 2022	The frequency of this variant in the general population, 0.0000081 (2/248256 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In vitro studies have shown that Hb Manitoba I is mildly unstable and has reduced dissociation (PMID: 7803274 (1994), 5452728 (1970)). Individuals heterozygous for this variant have a normal clinical presentation, with Hb Manitoba I accounting for 19% of total hemoglobin (PMID: 11791879 (2001), 7803274 (1994), 6547932 (1984), 5452728 (1970)). 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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 09, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.17	N
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.093	T
MutationTaster	Benign	0.95	N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.023	D;D
Vest4		0.76
MutPred		0.96		Gain of catalytic residue at S103 (P = 0.0654);.;
MVP		1.0
MPC		1.7
ClinPred		0.82	D
GERP RS		0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.94

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: rs41321052; hg19: chr16-223477;