rs41341344

Positions:

• chr16-173001-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000517.6(HBA2):​c.89T>C​(p.Leu30Pro) variant causes a missense 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: 3)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 2.95

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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 16-173001-T-C is Pathogenic according to our data. Variant chr16-173001-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 15651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.89T>C	p.Leu30Pro	missense_variant	1/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.89T>C	p.Leu30Pro	missense_variant	1/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000484216.1	c.59T>C	p.Leu20Pro	missense_variant	1/2	1		ENSP00000495899
HBA2	ENST00000482565.1	n.108T>C		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.-2+43T>C		intron_variant		2		ENSP00000380908

Frequencies

GnomAD3 genomes Cov.: 3

GnomAD4 exome AF: 0.00000228 AC: 1 AN: 437880 Hom.: 0 Cov.: 0 AF XY: 0.00000434 AC XY: 1 AN XY: 230538

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: 0.00000381

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 09, 2022	The HBA2 c.89T>C; p.Leu30Pro variant (also known as Hb Agrinio or Leu29Pro when numbered from the mature protein, rs41341344, HbVar ID:45) has been reported in multiple individuals with microcytosis and hypochromia when found in a heterozygous state (de la Fuente-Gonzalo 2012, Hall 1993). Individuals homozygous for this variant or compound heterozygous with another pathogenic variant exhibit marked hypochromic microcytic anemia, with an elevated reticulocyte count and occasionally elevated Hb Barts or Hb H (de la Fuente-Gonzalo 2012, Hall 1993). This variant is also reported in ClinVar (Variation ID: 15651), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 30 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.910). In vitro studies show the variant protein is undetectable by various analyses, suggestive of an unstable hemoglobin variant (Hall 1993). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html de la Fuente-Gonzalo F et al. Study of three families with Hb Agrinio (alpha29(B10)Leu?Pro, CTG>CCG (alpha2)) in the Spanish population: three homozygous cases. Hemoglobin. 2012; 36(6):526-32. Hall G et al. A base substitution (T-->C) in codon 29 of the alpha 2-globin gene causes alpha thalassaemia. Br J Haematol. 1993; 85(3):546-52. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 27, 2022	The c.89T>C (p.Leu30Pro) mutation in the alpha2-globin gene is known as Hb Agrinio. Hb Agrinio is reported as being hyperunstable. Individuals who are heterozygous for this variant are reported as having a normal clinical presentation (PMID: 8537235 (1995)). However, individuals who are homozygous for this variant, or compound heterozygous for this variant and a mutation associated with alpha-thalassemia, often present with atypical Hb H disease (PMIDs: 36052950 (2022), 29219637 (2017), 23094635 (2012), 22452522 (2012), 20854116 (2010), 9629496 (1998), 8537235 (1995), and 8136277 (1993)). -

alpha Thalassemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 08, 2024

Variant summary: HBA2 c.89T>C (p.Leu30Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-06 in 446884 control chromosomes (gnomAD v4.1). c.89T>C has been reported in the literature in the simple heterozygous state in individuals with alpha thalassemia and in compound heterozygotes with an atypical form of HbH disease characterized by a severe hypochromic microcytic anaemia (Hall_1993). It was also found in the homozygous state in multuple cases of severe antenatal anemia (Szepetowski_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36052950, 8136277). ClinVar contains an entry for this variant (Variation ID: 15651). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hemoglobin H disease, nondeletional Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1998

- -

HEMOGLOBIN AGRINIO Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.93
MutPred		0.94		Gain of glycosylation at L30 (P = 0.0144);
MVP		1.0
MPC		3.2
ClinPred		1.0	D
GERP RS		3.9
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs41341344; hg19: chr16-223000;