NM_000558.5:c.186G>T

Variant names:

• chr16-177019-G-T
• rs281864775
• NM_000558.5:c.186G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000558.5(HBA1):​c.186G>T​(p.Lys62Asn) 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. K62T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HBA1 NM_000558.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0560
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• alpha thalassemia spectrum

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hemoglobin M disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hb Bart's hydrops fetalis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin H disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Heinz body anemia

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000294436 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a glycosylation_site N-linked (Glc) (glycation) lysine (size 0) in uniprot entity HBA_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA1	NM_000558.5	c.186G>T	p.Lys62Asn	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.186G>T	p.Lys62Asn	missense_variant	Exon 2 of 3	1	NM_000558.5	ENSP00000322421.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb J-Buda variant (HBA1: c.186G>T; p.Lys62Asn, also known as Lys61Asn when numbered from the mature protein, rs281864775, HbVar ID: 90, ClinVar Variation ID: 1330840) is reported in the literature in siblings affected with erythrocytosis who also carry the Hb G-Pest variant (HBA1: c.223G>A; p.Asp75Asn), and in the heterozygous state in their healthy offspring (see link to HbVar, Hollan 1972). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.752). Due to limited information, the clinical significance of the Hb J-Buda variant is uncertain at this time. References: Link to HbVar Database: https://globin.bx.psu.edu/hbvar/menu.html Hollan SR et al. Multiple alpha chain loci for human haemoglobins: Hb J-Buda and Hb G-Pest. Nature. 1972 Jan 7;235(5332):47-50. PMID: 4550395. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.74	D
PhyloP100		0.056
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.016	D;D
Vest4		0.70
MutPred		0.94		Loss of ubiquitination at K62 (P = 0.0496);.;
MVP		1.0
ClinPred		1.0	D
GERP RS		2.3
PromoterAI		-0.027	Neutral
Varity_R		0.96
gMVP		0.91

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

Other links and lift over

dbSNP: rs281864775; hg19: chr16-227018;