16-173598-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM4PP5_Very_Strong

The NM_000517.6(HBA2):c.427T>C(p.Ter143Glnext*?) variant causes a stop lost change. The variant allele was found at a frequency of 0.0000224 in 1,608,260 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

HBA2
NM_000517.6 stop_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:3

Conservation

PhyloP100: 4.12

Variant links:

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 links:

ENSG00000290038 (HGNC:):

ENSG00000290038 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM4

Stoplost variant in NM_000517.6 Downstream stopcodon found after 154 codons.

PP5

Variant 16-173598-T-C is Pathogenic according to our data. Variant chr16-173598-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 15624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-173598-T-C is described in Lovd as [Pathogenic]. Variant chr16-173598-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.427T>C	p.Ter143Glnext*?	stop_lost	Exon 3 of 3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11 link	c.427T>C	p.Ter143Glnext*?	stop_lost	Exon 3 of 3	1	NM_000517.6	ENSP00000251595.6		P69905

Frequencies

GnomAD3 genomes

AF:

0.0000403

AC:

AN:

149046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000969

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

GnomAD3 exomes

AF:

0.0000563

AC:

AN:

248854

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

134854

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000601

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000206

AC:

AN:

1459094

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725622

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.0000235

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000402

AC:

AN:

149166

Hom.:

Cov.:

AF XY:

0.0000274

AC XY:

AN XY:

72884

show subpopulations

Gnomad4 AFR

AF:

0.0000257

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000972

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000594

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000496

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

alpha Thalassemia

Pathogenic:6Other:2

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0208 - Variant is predicted to result in an elongated protein (exon 3 of 3). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (P) 0702 - Comparable variants have strong previous evidence for pathogenicity (ClinVar). Four other elongated protein have been reported as pathogenic. (P) 0801 - Strong previous evidence of pathogenicity in multiple unrelated individuals. This is the most common pathogenic mutation reported in alpha thalassemia, known as the Hb Constant Sprint variant (ClinVar, PMID: 26757782). (P) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Sep 02, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000517.4(HBA2):c.427T>C(*143Qext*31, aka Hb Constant Spring) is classified as pathogenic in the context of alpha thalassemia and is classified as an alpha-plus variant. Sources cited for classification include the following: PMID 4944483, 12393486, 7327587, 2298455 and 17164653. Classification of NM_000517.4(HBA2):c.427T>C(*143Qext*31, aka Hb Constant Spring) is based on the following criteria: This variant is predicted to result in protein elongation in a gene and is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 07-24-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Jul 27, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM1, PM4, PP1, PP5 -

Mar 15, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Stop lost variant The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015624 /PMID: 3177365). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:5

Sep 19, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBA2 c.427T>C (p.*143Glnext*31) variant disrupts the translation stop codon of the HBA2 mRNA and is predicted to cause abnormal HBA2 protein elongation. In the published literature and online databases, this variant has been reported to be damaging to HBA2 function and results in an unstable protein (PMID: 7969150 (1994)). Additionally, this variant has been reported in individuals with Hb H disease that are compound heterozygous with other pathogenic HBA2 variants, such as Hb Adana (PMIDs: 24829075 (2014), 27271331 (2016)), Hb Pakse (PMIDs: 7502632 (1995), 28244614 (2018), 30615015 (2019)), and Hb Quong (PMID: 26956449 (2016)). This variant is commonly seen with the SEA alpha-1 deletion (PMIDs: 11836160 (2002), 32925409 (2021), 36459106 (2023)). Based on the available information, this variant is classified as pathogenic. -

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Constant Spring variant (HbCS, HBA2: c.427T>C; p.Ter143Gln, also known as Ter142Gln when numbered from the mature protein, rs41464951, HbVar ID: 703) is usually asymptomatic in the heterozygous state, but may be associated with microcytosis and mild hypochromia. Homozygosity for HbCS is characterized by overt hemolytic anemia, jaundice and splenomegaly, while HbCS paired with an alpha zero-thalassemia deletion commonly results in HbH disease (Lie-Injo 1974, Nguyen 2014, HbVar database). This variant is reported in ClinVar (Variation ID: 15624), and is found in the general population with an overall allele frequency of 0.006% (16/279,508 alleles) in the Genome Aggregation Database. This variant abolishes the canonical termination codon, resulting in an unstable, elongated protein (HbVar database). Based on available information, the HbCS variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Lie-Injo L et al. Homozygous state for Hb Constant Spring (slow-moving Hb X components). Blood. 1974 Feb;43(2):251-9. PMID: 4810076. Nguyen V 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 Apr;52(4):161-5. PMID: 24368026. -

Apr 03, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also known as Hb-CS, Hemoglobin-Constant Spring; The variant eliminates the normal Stop codon and replaces it with a Glutamine codon, ultimately extending the protein by 31 amino acids at the C-terminal end of the protein; This variant is associated with the following publications: (PMID: 24368026, 21077767, 24829075, 25523870, 23637094, 20931520, 3177365, 25897478, 26956449, 30626226, 30615015, 30275481, 34272389, 32925409, 32860378, 32338097, 26351923, 37311260, 31286593, 29627922, 35314707, 28244614, 28674233, 38167091, 7969150, 36282478, 6725554, 9057661, 26757782, 11836160) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change disrupts the translational stop signal of the HBA2 mRNA. It is expected to extend the length of the HBA2 protein by 31 additional amino acid residues. This variant is present in population databases (rs41464951, gnomAD 0.07%). This protein extension has been observed in individual(s) with HBA2-related conditions (PMID: 2298455, 4944483, 12393486, 20507641). It is commonly reported in individuals of Southeast Asian ancestry (PMID: 2298455, 4944483, 12393486, 20507641). This variant is also known as Constant Spring. ClinVar contains an entry for this variant (Variation ID: 15624). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this protein extension affects HBA2 function (PMID: 6725554, 9057661). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:2

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM4+PS3_Supporting+PM3_VeryStrong+PP4 -

May 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hemoglobin H disease, nondeletional

Pathogenic:1

Jan 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hemoglobin constant spring

Other:1

Sep 12, 2022

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.85

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

Vest4

0.16

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over