rs281864560

chr16-173001-TGGA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_000517.6(HBA2):c.91_93del(p.Glu31del) variant causes a inframe deletion 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: 3)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 0.984

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000517.6
• PM4: Nonframeshift variant in NON repetitive region in NM_000517.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-173001-TGGA-T is Pathogenic according to our data. Variant chr16-173001-TGGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.91_93del	p.Glu31del	inframe_deletion	1/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.91_93del	p.Glu31del	inframe_deletion	1/3	1	NM_000517.6	P1
HBA2	ENST00000484216.1	c.60_62del	p.Glu21del	inframe_deletion	1/2	1
HBA2	ENST00000482565.1	n.110_112del		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.-2+45_-2+47del		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 9042 Hom.: 0 Cov.: 3 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

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 9042 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 4192

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: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 12, 2023	The HBA2 c.91_93delGAG; p.Glu31del variant (also known as codon 30 (-GAG) or as Glu30del when numbered from the mature protein, rs281864560, HbVar ID: 2776) is reported in the literature in multiple individuals affected with Hb H disease in trans to large deletions of HBA1 and HBA2 (Chan 1997, Chen 2000, Yang 2013). The p.Glu31del variant is also reported in heterozygous individuals with mild microcytosis and hypochromia (Yang 2013, HbVar database). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single glutamate residue, leaving the rest of the protein in-frame. Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Chan V et al. Molecular defects in Hb H hydrops fetalis. Br J Haematol. 1997 Feb;96(2):224-8. PMID: 9029003. Chen FE et al. Genetic and clinical features of hemoglobin H disease in Chinese patients. N Engl J Med. 2000 Aug 24;343(8):544-50. PMID: 10954762. Yang Y and Li DZ. CODON 30 (-GAG) (a2): hematological parameters in heterozygotes and also patients with Hb H disease. Hemoglobin. 2013;37(6):599-603. PMID: 23822871. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 08, 2017	- -

HEMOGLOBIN H HYDROPS FETALIS SYNDROME Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs281864560; hg19: chr16-223000;