rs41321345

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM4PP5_Very_Strong

The NM_000517.6(HBA2):c.428A>C(p.Ter143SerextTer31) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HBA2
NM_000517.6 stop_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 1.21

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 16-173599-A-C is Pathogenic according to our data. Variant chr16-173599-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15627.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 linkuse as main transcript	c.428A>C	p.Ter143SerextTer31	stop_lost	3/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HBA2	ENST00000251595.11 linkuse as main transcript	c.428A>C	p.Ter143SerextTer31	stop_lost	3/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000482565.1 linkuse as main transcript	n.564A>C		non_coding_transcript_exon_variant	2/2	1
	ENST00000702607.1 linkuse as main transcript	n.62T>G		non_coding_transcript_exon_variant	1/1
HBA2	ENST00000397806.1 linkuse as main transcript	c.332A>C	p.Ter111SerextTer31	stop_lost	3/3	2		ENSP00000380908

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248882

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459116

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725626

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000235

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2021	The Hb Koya Dora variant (HBA2: c.428A>C; p.Ter143SerextTer31 also known as Ter142Ser when numbered from the mature protein, rs41321345) is reported in the heterozygous state associated with mild anemia and hypochromia (see link to HbVar). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant abolishes the canonical termination codon, resulting in an elongated protein that is unstable, similar to other stop loss variants (Hb Constant Spring, Hb Icaria)(see HbVar links and references therein). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database for Hb Koya Dora: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=705&.cgifields=histD Link to HbVar database for Hb Constant Spring: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=703&.cgifields=histD Link to HbVar database for Hb Icaria: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=704&.cgifields=histD -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 03, 2022	This variant disrupts the translation stop codon of the HBA2 mRNA and is predicted to cause HBA2 protein elongation. The frequency of this variant in the general population, 0.000004 (1/248882 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been associated with alpha-thalassemia (PMIDs: 26365411 (2015), 19373587 (2009), 1802886 (1991), 1155453 (1975)). Based on the available information, this variant is classified as pathogenic. -

alpha Thalassemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The stop lost c.428A>C p.Ter143SerextTer31 variant in the HBA2 gene has been reported in compound heterozygous state in a patient with Alpha-thalassemia Deshpande, Prashant et al., 2015. This variant is reported with the allele frequency 0.0004% in the gnomAD Exomes and novel in 1000 Genomes. The variant is reported to ClinVar as Pathogenic. The p.Ter143SerextTer31 variant in the stop codon Ter/* at position 143, changing it to a Serine-codon a no-stop variant and adding a tail of new amino acids to the protein’s C-terminus, ending at a new stop codon Ter/* at position 31. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. The amino acid change p.Ter143SerextTer31 in HBA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Functional studies are required to prove the pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. -

HEMOGLOBIN KOYA DORA

Other:1

other, no assertion criteria provided

literature only

OMIM

Mar 28, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.74

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

N;N

Vest4

0.16

GERP RS

2.2

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