rs1270810159

Positions:

chr16-172980-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_000517.6(HBA2):c.69delC(p.Glu24fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 2)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -3.95

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:

HBA2 (HGNC:):

HBA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.

PP5

Variant 16-172980-GC-G is Pathogenic according to our data. Variant chr16-172980-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-172980-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.69delC	p.Glu24fs	frameshift_variant	1/3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HBA2	ENST00000251595.11 linkuse as main transcript	c.69delC	p.Glu24fs	frameshift_variant	1/3	1	NM_000517.6	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1 linkuse as main transcript	c.36delC	p.Glu13fs	frameshift_variant	1/2	1		ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1 linkuse as main transcript	n.88delC		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1 linkuse as main transcript	c.-2+23delC		intron_variant		2		ENSP00000380908.1	G3V1N2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

5238

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000561

AC:

AN:

53510

Hom.:

AF XY:

0.0000742

AC XY:

AN XY:

26968

show subpopulations

Gnomad AFR exome

AF:

0.000408

Gnomad AMR exome

AF:

0.0000950

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000956

AC:

AN:

418318

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

219956

show subpopulations

Gnomad4 AFR exome

AF:

0.000196

Gnomad4 AMR exome

AF:

0.0000554

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:

0.00

Gnomad4 OTH exome

AF:

0.0000417

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

5238

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

2548

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 13, 2021	This variant causes the premature termination of HBA2 protein synthesis, and has been reported in heterozygous carriers with mild microcytic anemia in the published literature (PMIDs: 16512835 (2006) and 17486494 (2007)). Functional studies showed that this variant does not affect RNA splicing, but the mRNA transcript is subject to nonsense-mediated decay (PMID: 16512835 (2006)). Therefore, the variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as CD22(-C); This variant is associated with the following publications: (PMID: 20507641, 16512835, 31025160, 17486494) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2022	The HBA2 c.69delC; p.Glu24SerfsTer26 variant (rs1270810159), also known as codon 22 (-C), is reported in the literature in the heterozygous state in individuals with microcytic and hypochromic anemia (Luo 2007, Pereira 2006). This variant is also reported in ClinVar (Variation ID: 439123). This variant is found in the general population with an overall allele frequency of 0.006% (3/53510 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, and has been shown to result in a truncated mRNA subject to nonsense-mediated decay (Pereira 2006). Based on available information, this variant is considered to be pathogenic. References: Luo HY et al. Two new alpha-thalassemia frameshift mutations. Hemoglobin. 2007;31(2):135-9. PMID: 17486494. Pereira FJ et al. Human alpha2-globin nonsense-mediated mRNA decay induced by a novel alpha-thalassaemia frameshift mutation at codon 22. Br J Haematol. 2006 Apr;133(1):98-102. PMID: 16512835. -

alpha Thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

May 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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