NM_000558.5:c.181A>C

Variant names:

• chr16-177014-A-C
• NM_000558.5:c.181A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000558.5(HBA1):​c.181A>C​(p.Lys61Gln) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K61N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.243

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.181A>C	p.Lys61Gln	missense_variant	Exon 2 of 3	ENST00000320868.9	NP_000549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA1	ENST00000320868.9	c.181A>C	p.Lys61Gln	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5
HBA1	ENST00000472694.1	n.317A>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA1	ENST00000487791.1	n.150A>C		non_coding_transcript_exon_variant	Exon 2 of 2	1
HBA1	ENST00000397797.1	c.85A>C	p.Lys29Gln	missense_variant	Exon 2 of 3	2		ENSP00000380899.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 17

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 29, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBA1 c.181A>C (p.Lys61Gln) variant, to the best of our knowledge, has not been reported in the published literature. It also 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
AlphaMissense	Benign	0.073
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.22	D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N;N
REVEL	Pathogenic	0.66
Sift	Benign	0.10	T;T
Sift4G	Benign	0.21	T;T
Vest4		0.58
MutPred		0.33		Loss of ubiquitination at K61 (P = 0.0412);.;
MVP		1.0
ClinPred		0.47	T
GERP RS		-3.7
Varity_R		0.34
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-227013;