16-173548-T-C

Variant names:

• chr16-173548-T-C
• rs41397847
• NM_000517.6:c.377T>C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000517.6(HBA2):​c.377T>C​(p.Leu126Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,458,978 control chromosomes in the GnomAD database, including 1 homozygotes. 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. L126Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000089 (1 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 2.78
• Publications: 10 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 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000517.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-173548-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 869221.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 16-173548-T-C is Pathogenic according to our data. Variant chr16-173548-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 15630.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.377T>C	p.Leu126Pro	missense_variant	Exon 3 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.377T>C	p.Leu126Pro	missense_variant	Exon 3 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes AF: 0.00000673 AC: 1 AN: 148660 Hom.: 0 Cov.: 26

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

GnomAD2 exomes AF: 0.0000563 AC: 14 AN: 248696 AF XY: 0.0000445

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000710

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000891 AC: 13 AN: 1458978 Hom.: 1 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 725562

African (AFR) AF: 0.00 AC: 0 AN: 32118

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 85164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111874

Other (OTH) AF: 0.0000332 AC: 2 AN: 60260

GnomAD4 genome Cov.: 26

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Feb 16, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also known as Hb Quong Sze, Hb QS, p.L125P; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect and results in an unstable hemoglobin alpha molecule (PMID: 6826718); This variant is associated with the following publications: (PMID: 7070526, 34334003, 36059093, 32830468, 36900038, 26956449, 22589661, 28674233, 21797711, 1726096, 909565, 30275481, 19259674, 31553106, 25523870, 38123349, 24081251, 32811243, 28865746, 7515267, 23383304, SuwannasingS2016[Article], 32436451, 38112059, 32473995, 36685902, 24985555, 20144601, 32338097, 28125089, 11325652, Vijian2022[Review], 31111755, 24826791, WidyastitiNS2019[Article], 25352644, 6826718) -

Jul 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Quong Sze variant (HBA2: c.377T>C; p.Leu126Pro, also known as Leu125Pro when numbered from the mature protein, rs41397847, HbVar ID: 187) is reported in the literature in multiple Chinese individuals and families affected with alpha thalassemia (see link to HbVar and references therein). This variant has been observed in the heterozygous state in individuals with a clinical presentation resembling alpha-thalassemia trait, and in the compound heterozygous state with other pathogenic hemoglobin variants in individuals affected with hemoglobin H disease (Ahmad 2013, Goossens 1982, He 2017, Li 2011, Li 2015, Liang 1994, Liao 2009, Shang 2017, Zhou 2016). In vitro/in vivo functional analyses demonstrate that the variant protein is turned over rapidly and interferes with the formation of hemoglobin tetramers (Liebhaber 1983). This variant is reported in ClinVar (Variation ID: 15630). This variant is found in the East Asian population with an overall allele frequency of 0.08% (13/18322 alleles, including a single homozygote) in the Genome Aggregation Database. Additionally, other variants at this codon Hb West-Einde (HbVar ID: 2592), and Hb Plasencia (HbVar ID: 1226) have been reported in individuals with mild to moderate anemia, microcytosis, and hypochromia (see links to HbVar and references therein). The leucine at codon 126 is weakly conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.854). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html Ahmad R et al. Distribution of alpha thalassaemia gene variants in diverse ethnic populations in malaysia: data from the institute for medical research. Int J Mol Sci. 2013 Sep 10;14(9):18599-614. PMID: 24025420 Goossens M et al. Globin structural mutant alpha 125Leu leads to Pro is a novel cause of alpha-thalassaemia. Nature. 1982 Apr 29;296(5860):864-5. PMID: 7070526 He J et al. Next-generation sequencing improves thalassemia carrier screening among premarital adults in a high prevalence population: the Dai nationality, China. Genet Med. 2017 Sep;19(9):1022-1031. PMID: 28125089 Li J et al. Phenotypic variability in a chinese family with nondeletional Hb H-Hb Quong Sze disease. Hemoglobin. 2011;35(4):430-3. PMID: 21797711 Li J et al. Identification of nondeletional a-thalassemia in a prenatal screening program by reverse dot-blot in southern China. Hemoglobin. 2015;39(1):42-5. PMID: 25523870 Liang R et al. Alpha and beta thalassaemia among Chinese children in Guangxi Province, P.R. China: molecular and haematological characterization. Br J Haematol. 1994 Feb;86(2):351-4. PMID: 7515267 Liao C et al. Diversity in clinical presentation of hemoglobin H disease induced by the SEA deletion and the hemoglobin Quong Sze. Ann Hematol. 2009 Nov;88(11):1145-7. PMID: 19259674 Liebhaber SA et al. alpha-Thalassemia caused by an unstable alpha-globin mutant. J Clin Invest. 1983 Mar;71(3):461-6. PMID: 6826718 Shang X et al. Rapid Targeted Next-Generation Sequencing Platform for Molecular Screening and Clinical Genotyping in Subjects with Hemoglobinopathies. EBioMedicine. 2017 Sep;23:150-159. PMID: 28865746 Zhou JY et al. First Case of a Compound Heterozygosity for Two Nondeletional a-Thalassemia mutations, Hb Constant Spring and Hb Quong Sze. Hemoglobin. 2016 Jun;40(3):210-2. PMID: 26956449 -

Apr 14, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.377T>C (p.Leu126Pro) pathogenic variant (also known as Hb Quong Sze) is reported as being highly unstable (PMID: 6826718 (1983), 1726096 (1991)). The frequency of this variant in the general population, 0.00071 (13/18322 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals who are compound heterozygous for this pathogenic variant and a large deletion that removes both of the alpha-globin genes from the alpha-globin gene cluster (e.g., the --SEA alpha-globin deletion) are reported as being affected by Hb H disease (PMID: 7070526 (1982), 7515267 (1994), 19259674 (2009)). -

alpha Thalassemia Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 08, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7 Pathogenic:1

Jun 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hemoglobin Quong Sze Other:1

Mar 28, 2013

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.67	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.70	D
PhyloP100		2.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Vest4		0.89
MutPred		0.97		Loss of stability (P = 0.0055);.;
MVP		1.0
MPC		3.2
ClinPred		0.90	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.98
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs41397847; hg19: chr16-223547;