rs34751764

Positions:

• chr16-176732-G-A
• chr16-176732-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000558.5(HBA1):​c.16G>A​(p.Ala6Thr) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0960

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]

HBA1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19341373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA1	NM_000558.5	c.16G>A	p.Ala6Thr	missense_variant	1/3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.16G>A	p.Ala6Thr	missense_variant	1/3	1	NM_000558.5	ENSP00000322421.5
HBA1	ENST00000472694.1	n.35G>A		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000397797	c.-32G>A		5_prime_UTR_variant	1/3	2		ENSP00000380899.1
HBA1	ENST00000487791.1	n.-16G>A		upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000139 AC: 2 AN: 1443332 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 716870

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000516

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.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 28, 2024

The HBA1 c.16G>A (p.Ala6Thr) variant (also known as Hb Hengqin I) has been reported in the published literature in a pregnant female with moderate anemia symptoms (PMID: 36099017 (2022)) as well as in reportedly healthy individuals (PMID: 36226750 (2022)). The frequency of this variant in the general population, 0.0000095 (2/209524 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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	Benign	0.076
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.0028	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.52
Sift	Benign	0.15	T
Sift4G	Benign	0.49	T
Vest4		0.17
MutPred		0.24		Gain of glycosylation at A6 (P = 0.042);
MVP		1.0
ClinPred		0.066	T
GERP RS		1.4
Varity_R		0.15
gMVP		0.49

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: rs34751764; hg19: chr16-226731;