rs63750678

Variant names:

• chr16-172913-AT-A
• rs63750678
• NM_000517.6:c.2delT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PS1_Moderate PP5_Very_Strong

The NM_000517.6(HBA2):​c.2delT​(p.Met1ArgfsTer49) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: HBA2 NM_000517.6 frameshift, start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.03
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• alpha thalassemia spectrum

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• erythrocytosis, familial, 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hemoglobin M disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hb Bart's hydrops fetalis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin H disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Heinz body anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• methemoglobinemia, alpha type

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000294455 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 82 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_000517.6 (HBA2) was described as [Pathogenic] in ClinVar
• PP5: Variant 16-172913-AT-A is Pathogenic according to our data. Variant chr16-172913-AT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 15692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000517.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	NM_000517.6	MANE Select	c.2delT	p.Met1ArgfsTer49	frameshift start_lost	Exon 1 of 3	NP_000508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	ENST00000251595.11	TSL:1 MANE Select	c.2delT	p.Met1ArgfsTer49	frameshift start_lost	Exon 1 of 3	ENSP00000251595.6
	HBA2	ENST00000482565.1	TSL:1	n.21delT		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000294455	ENST00000723699.1		n.209delA		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000744 AC: 2 AN: 268920 Hom.: 0 Cov.: 0 AF XY: 0.00000698 AC XY: 1 AN XY: 143308

African (AFR) AF: 0.00 AC: 0 AN: 6640

American (AMR) AF: 0.00 AC: 0 AN: 13128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7414

East Asian (EAS) AF: 0.000136 AC: 2 AN: 14680

South Asian (SAS) AF: 0.00 AC: 0 AN: 42036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1018

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 155676

Other (OTH) AF: 0.00 AC: 0 AN: 14226

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	alpha Thalassemia (1)
1	-	-	alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7 (1)
1	-	-	Hemoglobin H disease, nondeletional (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=17/183	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs63750678; hg19: chr16-222912;