rs34098449

Positions:

• chr16-177291-C-A
• chr16-177291-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM2 PP3_Strong BP6

The NM_000558.5(HBA1):​c.309C>A​(p.Ser103Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.345

Genes affected

HBA1 (HGNC:4823): (hemoglobin subunit alpha 1) 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]

ENSG00000290010 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• BP6: Variant 16-177291-C-A is Benign according to our data. Variant chr16-177291-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1330740.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	Protein	UniProt
HBA1	NM_000558.5	c.309C>A	p.Ser103Arg	missense_variant	3/3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.309C>A	p.Ser103Arg	missense_variant	3/3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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	Jun 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 05, 2024	The HBA1 c.309C>A (p.Ser103Arg) variant has been reported in the published literature in individuals who are homozygous and heterozygous for the variant with hematological indices ranging from normal to alpha thalassemia silent carriers and alpha thalassemia trait carriers (PMIDs: 87 (1975), 6547932 (1984), 7803274 (1994)). One individual was diagnosed with macrocytic anemia (PMID: 5452728 (1970)). Evidence surrounding the variant's impact on protein function is conflicting as to whether or not the variant is mildly unstable with decreased dissociation or stable with asymmetric hemoglobin hybrids (PMIDs: 87 (1975), 6547932 (1984); HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter) and ITHANET (http://www.ithanet.eu/)). 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 benign or damaging. 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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.67	T;T
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.49	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.023	D;D
Vest4		0.75
MutPred		0.96		Gain of catalytic residue at S103 (P = 0.0654);.;
MVP		1.0
ClinPred		0.74	D
GERP RS		2.4
Varity_R		0.84
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34098449; hg19: chr16-227290;