rs1277780626

Variant names:

• chr16-172854-C-T
• rs1277780626
• NM_000517.6:c.-59C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000517.6(HBA2):​c.-59C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0026 (12 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBA2 NM_000517.6 upstream_gene
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.459
• 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, ClinGen, 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
• unstable hemoglobin disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000294455 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00261 (332/127138) while in subpopulation AMR AF = 0.0325 (230/7070). AF 95% confidence interval is 0.0291. There are 12 homozygotes in GnomAdExome4. There are 144 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	NM_000517.6	MANE Select	c.-59C>T		upstream_gene	N/A	NP_000508.1	D1MGQ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	ENST00000251595.11	TSL:1 MANE Select	c.-59C>T		upstream_gene	N/A	ENSP00000251595.6	P69905
	HBA2	ENST00000484216.1	TSL:1	c.-92C>T		upstream_gene	N/A	ENSP00000495899.1	A0A2R8Y7C0
	HBA2	ENST00000482565.1	TSL:1	n.-40C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AC: 0 AN: 0 Hom.: 0 Cov.: 0

GnomAD4 exome AF: 0.00261 AC: 332 AN: 127138 Hom.: 12 Cov.: 0 AF XY: 0.00215 AC XY: 144 AN XY: 67122

African (AFR) AF: 0.00 AC: 0 AN: 2968

American (AMR) AF: 0.0325 AC: 230 AN: 7070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2834

East Asian (EAS) AF: 0.000332 AC: 2 AN: 6032

South Asian (SAS) AF: 0.00 AC: 0 AN: 20328

European-Finnish (FIN) AF: 0.00481 AC: 26 AN: 5402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 450

European-Non Finnish (NFE) AF: 0.000595 AC: 45 AN: 75578

Other (OTH) AF: 0.00448 AC: 29 AN: 6476

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

Alfa AF: 0.000590 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7 (1)
-	1	-	HBA2-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.1
DANN	Benign	0.78
PhyloP100		-0.46
PromoterAI		0.066	Neutral
Mutation Taster		=124/176	disease causing

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

Other links and lift over

dbSNP: rs1277780626; hg19: chr16-222853;