rs41464951

Positions:

• chr16-173598-T-A
• chr16-173598-T-C
• chr16-173598-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_000517.6(HBA2):​c.427T>A​(p.Ter143LysextTer31) variant causes a stop lost change. The variant allele was found at a frequency of 0.00000206 in 1,459,094 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HBA2 NM_000517.6 stop_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 4.12

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000517.6 Downstream stopcodon found after 154 codons.
• PP5: Variant 16-173598-T-A is Pathogenic according to our data. Variant chr16-173598-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 15626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.427T>A	p.Ter143LysextTer31	stop_lost	3/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.427T>A	p.Ter143LysextTer31	stop_lost	3/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000482565.1	n.563T>A		non_coding_transcript_exon_variant	2/2	1
	ENST00000702607.1	n.63A>T		non_coding_transcript_exon_variant	1/1
HBA2	ENST00000397806.1	c.331T>A	p.Ter111LysextTer31	stop_lost	3/3	2		ENSP00000380908

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459094 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725622

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

alpha Thalassemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2024	Variant summary: HBA2 c.427T>A (p.X143LysextX31) changes the termination codon and is predicted to lead to an extended protein with additional amino acids added to the normal C-terminus. HBA2 c.427T>A (p.X143LysextX31) causes a frameshift which results in an extension of the protein. The variant was absent in 248854 control chromosomes. c.427T>A has been reported in the literature in individuals affected with Hemoglobin H disease (Hb-H) (examples: Efremov_1990, Kanavakis_1996, Kimura_2009). Other variant that results in a similarly extended protein product (p.(*143Tyrext*31) has been classified pathogenic by our lab and in ClinVar. These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 2372512, 21637442, 8602995). ClinVar contains an entry for this variant (Variation ID: 15626). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jul 30, 2024	The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Stop lost variant. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 21637442, 2372512, 8602995). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 2372512). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015626 / PMID: 21637442, 2372512, 8602995). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 25, 2019	The variant disrupts the natural stop codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 26, 2023	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 not present in population databases (gnomAD no frequency). This protein extension has been observed in individual(s) with hemoglobin H disease (PMID: 2372512, 8602995, 21637442). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Hb Icaria in literature. ClinVar contains an entry for this variant (Variation ID: 15626). This variant results in an extension of the HBA2 protein. Other variant(s) that result in a similarly extended protein product (p.*143Glnext*31) have been determined to be pathogenic (PMID: 2298455, 4944483, 12393486, 20507641). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

beta Thalassemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2022

The p.X143LysextX32 variant in HBA2 (also known as Hb-Icaria) has been reported in the compound heterozygous state (with a deletion) in at least 2 individuals with hemoglobin H disease and in carriers with haematological findings comparable to those with a deletional type of alpha-thalassaemia-2 (Efremov 1990 PMID: 2372512, Kanavakis 1996 PMID: 8602995, Kimura 2009 21637442). This variant has also been reported in ClinVar (Variation ID: 15626) and was absent from large population studies. This variant abolished the termination codon and results in an extension of the HBA2 protein. Additional variants that result in a similarly extended protein product have been reported in individuals with disease and have been classified as Pathogenic by multiple submitters in ClinVar. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hb H disease. ACMG/AMP Criteria applied: PM3 strong, PM2_supporting, PM4. -

Hemoglobin H disease, nondeletional Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1996

- -

HEMOGLOBIN ICARIA Other:1

other, no assertion criteria provided

literature only

OMIM

May 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	15
DANN	Benign	0.90
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	N;N
Vest4		0.16
GERP RS		4.4

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: rs41464951; hg19: chr16-223597;