rs41412046

chr16-173600-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000517.6(HBA2):c.429A>T(p.Ter143TyrextTer31) variant causes a stop lost change. The variant allele was found at a frequency of 0.0000067 in 149,166 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000067 (0 hom., cov: 25)
• Consequence: HBA2 NM_000517.6 stop_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.93

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-173600-A-T is Pathogenic according to our data. Variant chr16-173600-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 15652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.429A>T	p.Ter143TyrextTer31	stop_lost	3/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.429A>T	p.Ter143TyrextTer31	stop_lost	3/3	1	NM_000517.6	P1
HBA2	ENST00000482565.1	n.565A>T		non_coding_transcript_exon_variant	2/2	1
	ENST00000702607.1	n.61T>A		non_coding_transcript_exon_variant	1/1
HBA2	ENST00000397806.1	c.333A>T	p.Ter111TyrextTer31	stop_lost	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00000671 AC: 1 AN: 149044 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000670 AC: 1 AN: 149166 Hom.: 0 Cov.: 25 AF XY: 0.0000137 AC XY: 1 AN XY: 72872

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

alpha Thalassemia Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2023	Variant summary: HBA2 c.429A>T (p.X143TyrextX31) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. This variant is also known as Hb Pakse. Four other extensions variants disrupting this termination codon have been classified as pathogenic/likely pathogenic by ClinVar submitters. The variant was absent in 248852 control chromosomes (gnomAD). c.429A>T has been reported in the literature in multiple individuals affected with Alpha Thalassemia who were compound heterozygous with other pathogenic variants (Waye_1994, Sanchaisuriya_2002, Pornprasert_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8193381, 22881835, 12403487). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 19, 2023	The HBA2 c.429A>T (p.*143Tyrext*31) variant, also known as Hb Pakse, disrupts the translation stop codon of the HBA2 mRNA and is predicted to cause HBA2 protein elongation. This variant has been reported in the published literature in individuals compound heterozygous with the SEA alpha-1 deletion affected with Hb H disease (PMIDs: 8193381 (1994), 11836160 (2002)) and individuals compound heterozygous with Hb Adana (PMID: 27271331 (2016)) and Hb Constant Spring affected with alpha-thalassemia (PMIDs: 21077767 (2010), 27271331 (2016), 28244614 (2018), 30615015 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2023	The Hb Pakse variant (HBA2: c.429A>T; p.Ter143Tyr, also known as Ter142Tyr when numbered from the mature protein, rs41412046. HbVar ID: 707) has been described in multiple individuals with alpha-thalassemia (Nguyen 2014, Pichanun 2010, Waye 1994, HbVar database). Hb Pakse is one of the most prevalent non-deletion alpha-thalassemias in Southeast Asia (Singsanan 2007). This variant is listed in ClinVar (Variation ID: 15652), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant altered the canonical termination codon, and creates elongated, unstable mRNA that results in reduced alpha-chain synthesis (Waye 1994). Based on available information, the Hb Pakse variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Nguyen et al. Hemoglobin Constant Spring is markedly high in women of an ethnic minority group in Vietnam: a community-based survey and hematologic features. Blood Cells Mol Dis. 2014; 52(4):161-5. PMID: 24368026. Pichanun et al. Molecular screening of the Hbs Constant Spring (codon 142, TAA>CAA, alpha2) and Pakse (codon 142, TAA>TAT, alpha2) mutations in Thailand. Hemoglobin. 2010; 34(6):582-6. PMID: 21077767. Singsanan et al. Molecular characterization and origins of Hb Constant Spring and Hb Pakse in Southeast Asian populations. Ann Hematol. 2007; 86(9):665-9. PMID: 17589844. Waye et al. Identification of a novel termination codon mutation (TAA-->TAT, Term-->Tyr) in the alpha 2 globin gene of a Laotian girl with hemoglobin H disease. Blood. 1994; 83(11):3418-20. PMID: 8193381. -

Hemoglobin H disease, nondeletional Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	16
Dann	Benign	0.89
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	N;N
Vest4		0.16
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs41412046; hg19: chr16-223599;