rs41341344

Variant names:

• chr16-173001-T-C
• rs41341344
• NM_000517.6:c.89T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 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
• Publications: 1 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 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_000517.6
• 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 VariationId is 15651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.89T>C	p.Leu30Pro	missense_variant	Exon 1 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.89T>C	p.Leu30Pro	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6

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

African (AFR) AF: 0.00 AC: 0 AN: 10900

American (AMR) AF: 0.00 AC: 0 AN: 20144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13554

East Asian (EAS) AF: 0.00 AC: 0 AN: 30030

South Asian (SAS) AF: 0.00 AC: 0 AN: 45506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1872

European-Non Finnish (NFE) AF: 0.00000381 AC: 1 AN: 262226

Other (OTH) AF: 0.00 AC: 0 AN: 25032

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

Oct 27, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)).

Feb 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

alpha Thalassemia Pathogenic:1

Jul 08, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

HEMOGLOBIN AGRINIO Other:1

Sep 12, 2022

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
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
PhyloP100		2.9
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
ClinPred		1.0	D
GERP RS		3.9
PromoterAI		0.070	Neutral
gMVP		1.0
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs41341344; hg19: chr16-223000;