rs111033603

chr16-172914-T-Cchr16-172914-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PP5_Moderate

The NM_000517.6(HBA2):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: HBA2 NM_000517.6 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 2.03

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 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000517.6 (HBA2) was described as [Likely_pathogenic] in ClinVar as 3075919
• PP5: Variant 16-172914-T-C is Pathogenic according to our data. Variant chr16-172914-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 15643.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6	c.2T>C	p.Met1?	start_lost	1/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBA2	ENST00000251595.11	c.2T>C	p.Met1?	start_lost	1/3	1	NM_000517.6	P1
HBA2	ENST00000482565.1	n.21T>C		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.-46T>C		5_prime_UTR_variant	1/3	2
HBA2	ENST00000484216.1			upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000148 AC: 4 AN: 271088 Hom.: 0 Cov.: 0 AF XY: 0.0000138 AC XY: 2 AN XY: 144488

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000255

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

alpha Thalassemia Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1996	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 01, 2018	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 06, 2023

The HBA2 c.2T>C, p.Met1? variant, (also known as initiation codon (T->C), rs111033603, HbVar ID: 1061) has been reported in a heterozygous state in an individual with microcytic red blood cells (Ayala 1996), and with a double-gene deletion in a patient with HbH disease (Pirastu 1984). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The variant abolishes the canonical initiation codon of HBA2, and is predicted to result in an absent protein. Based on the above information, the variant is classified as pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.htmlAyala S et al. Ayala S et al. Nondeletional alpha-thalassemia: first description of alpha Hph alpha and alpha Nco alpha mutations in a Spanish population. Am J Hematol. 1996 Jul;52(3):144-9. PMID: 8756078. Pirastu M et al. Initiation codon mutation as a cause of alpha thalassemia. J Biol Chem. 1984 Oct 25;259(20):12315-7. PMID: 6490612. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	23
Dann	Uncertain	0.98
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.75	D
MutationTaster	Benign	1.0	A;A
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.86
MutPred		1.0		Loss of stability (P = 0.0171);
MVP		1.0
ClinPred		0.99	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111033603; hg19: chr16-222913;