rs34324664

chr16-176780-G-Achr16-176780-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000558.5(HBA1):c.64G>A(p.Ala22Thr) 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. A22D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.806

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35521907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA1	NM_000558.5	c.64G>A	p.Ala22Thr	missense_variant	1/3	ENST00000320868.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA1	ENST00000320868.9	c.64G>A	p.Ala22Thr	missense_variant	1/3	1	NM_000558.5	P1
HBA1	ENST00000472694.1	n.83G>A		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000487791.1	n.33G>A		non_coding_transcript_exon_variant	1/2	1
HBA1	ENST00000397797.1	c.-2+18G>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD3 exomes AF: 0.00000611 AC: 1 AN: 163732 Hom.: 0 AF XY: 0.0000114 AC XY: 1 AN XY: 88070

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: 0.0000423

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.98e-7 AC: 1 AN: 1432164 Hom.: 0 Cov.: 27 AF XY: 0.00000141 AC XY: 1 AN XY: 711298

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: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.17	D
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.016	D
Sift4G	Benign	0.16	T
Vest4		0.22
MutPred		0.52		Gain of phosphorylation at A22 (P = 0.0388);
MVP		1.0
ClinPred		0.12	T
GERP RS		1.2
Varity_R		0.28
gMVP		0.72

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: rs34324664; hg19: chr16-226779;