16-173159-T-G

Variant names:

• chr16-173159-T-G
• rs281864829
• NM_000517.6:c.130T>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_000517.6(HBA2):​c.130T>G​(p.Phe44Val) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F44L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 12)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.79
• Publications: 1 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: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_000517.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 16-173159-T-G is Pathogenic according to our data. Variant chr16-173159-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2428504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.130T>G	p.Phe44Val	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.130T>G	p.Phe44Val	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome Cov.: 9

GnomAD4 genome Cov.: 12

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Nov 15, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Torino variant (HBA2; c.130T>G; p.Phe44Val, also known as Phe43Val when numbered from the mature protein, rs281864829, HbVar ID: 55) is an unstable variant reported in the heterozygous state in the literature in multiple individuals affected with hemolytic anemia (see HbVar, Beretta 1968, Prato 1970). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Another variant at this codon (Hb Vanvitelli; p.Phe44Leu) has been reported in the compound heterozygous state in an individual with hemolytic anemia and is considered pathogenic (Casale 2019). The phenylalanine at codon 44 is highly conserved and computational analyses predict that this variant is deleterious (REVEL:0.95). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Beretta A et al. Haemoglobin Torino--alpha-43 (CD1) phenylalanine replaced by valine. Nature. 1968 Mar 16;217(5133):1016-8. PMID: 5643522. Casale M et al. Hb Vanvitelli: A new unstable a-globin chain variant causes undiagnosed chronic haemolytic anaemia when co-inherited with deletion?-?a3.7. Clin Biochem. 2019 Dec;74:80-85. PMID: 31493379. Prato V et al. Haemolytic anaemia due to haemoglobin Torino. Br J Haematol. 1970 Jul;19(1):105-15. PMID: 5453914. -

Thalassemia Pathogenic:1

Jan 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBA2 c.130T>G (p.Phe44Val), also known as Hb Toreno, results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 114748 control chromosomes (gnomAD). c.130T>G has been reported in the literature as an unstable hemoglobin variant in multiple heterozygous individuals affected with Hemolytic Anemia, with some cases described as suffering hemolytic crises following treatment with sulfonamides (e.g. Beretta_1968, Prato_1970, Sansone_1976, Stratta_1982, Castagnola_1988). These data indicate that the variant is very likely to be associated with disease. Other missense variants affecting this amino acid (p.Phe44Ile, p.Phe44Leu) have also been found in association with Hemolytic Anemia (PMID: 19815833, 31493379), supporting the clinical relevance of this residue. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in lower oxygen affinity (Ricco_1985). The following publications have been ascertained in the context of this evaluation (PMID: 5643522, 5453914, 3401329, 4041267, 826080, 7177688). ClinVar contains an entry for this variant (Variation ID: 2428504). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;T
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.93	D
PhyloP100		5.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.86
MutPred		0.95		Gain of phosphorylation at Y43 (P = 0.1277);.;
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		4.2
PromoterAI		0.0044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.99

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: rs281864829; hg19: chr16-223158;