rs281864845

Variant names:

• chr16-173204-C-T
• rs281864845
• NM_000517.6:c.175C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_000517.6(HBA2):​c.175C>T​(p.His59Tyr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H59Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 17)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.65
• Publications: 0 publications found

Genes affected

HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) 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]

HBA2 Gene-Disease associations (from GenCC):

• alpha thalassemia spectrum

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

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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
• Heinz body anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000294455 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 11 uncertain in NM_000517.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 16-173204-C-T is Pathogenic according to our data. Variant chr16-173204-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3346945.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.175C>T	p.His59Tyr	missense_variant	Exon 2 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.175C>T	p.His59Tyr	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Cov.: 13

GnomAD4 genome Cov.: 17

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

HBA2-related disorder Pathogenic:1

Jun 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HBA2 c.175C>T variant is predicted to result in the amino acid substitution p.His59Tyr. This variant, also described in the literature as the Hb M Boston variant or His58Tyr, is a known cause of autosomal dominant methemoglobinemia and cyanosis (Pulsinelli et al. 1973. PubMed ID: 4521212; Chen et al. 2020. PubMed ID: 33242448; Upadhye et al. 2015. PubMed ID: 25079170). Both inherited (Chen et al. 2020. PubMed ID: 33242448) and de novo occurrences have been documented (Shin et al. 2019. PubMed ID: 31269924). This variant has not been reported in a large population database, indicating this variant is rare. Other variants impacting the same amino acid (p.His59Leu and p.His59Gln), have also been documented in patients with HBA2-related disorders (Pedroso et al. 2019. PubMed ID: 31712880; Qadah et al. 2015. PubMed ID: 26193975). Based on this evidence, the c.175C>T (p.His59Tyr) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		5.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.57
MutPred		0.92		Loss of disorder (P = 0.0495);.;
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		3.2
PromoterAI		0.011	Neutral
gMVP		0.99
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs281864845; hg19: chr16-223203;