rs41529844

Positions:

chr16-173562-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_000517.6(HBA2):c.391G>C(p.Ala131Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,608,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A131D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 25)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:1

Conservation

PhyloP100: -0.204

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_000517.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 16-173562-G-C is Pathogenic according to our data. Variant chr16-173562-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15640.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.391G>C	p.Ala131Pro	missense_variant	3/3	ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HBA2	ENST00000251595.11 linkuse as main transcript	c.391G>C	p.Ala131Pro	missense_variant	3/3	1	NM_000517.6	P1
HBA2	ENST00000482565.1 linkuse as main transcript	n.527G>C		non_coding_transcript_exon_variant	2/2	1
	ENST00000702607.1 linkuse as main transcript	n.99C>G		non_coding_transcript_exon_variant	1/1
HBA2	ENST00000397806.1 linkuse as main transcript	c.295G>C	p.Ala99Pro	missense_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.00000672

AC:

AN:

148892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

248988

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000992

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1459136

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725642

show subpopulations

Gnomad4 AFR exome

AF:

0.0000311

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000672

AC:

AN:

148892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72674

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 01, 2021	The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a tolerated effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 08, 2023	The Hb Sun Prairie variant (HBA2: c.391G>C; p.Ala131Pro, also known as Ala130Pro when numbered from the mature protein, rs41529844, HbVar ID: 197) is a unstable hemoglobin reported in the literature in heterozygous individuals affected with microcytosis and hypochromia or with no symptoms (See HbVar and references therin). Homozygosity for Hb Sun Prairie is associated with Hb H disease and chronic hemolytic anemia (Hbvar, Farashi 2016, Jain 2021). This variant is also reported in ClinVar (Variation ID: 15640) and is found in the South Asian population with an allele frequency of 0.01% (3/30252 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Farashi S et al. Point mutations which should not be overlooked in Hb H disease. Expert Rev Hematol. 2016 Jan;9(1):107-13. PMID: 26523940. Jain A et al. Hb Sun Prairie: A rare cause of chronic hemolysis in an Indian patient. Hematol Oncol Stem Cell Ther. 2021 Sep;14(3):257-259. PMID: 32199931. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 02, 2023

Variant summary: HBA2 c.391G>C (p.Ala131Pro), also known as Hb Sun Prairie results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 248988 control chromosomes. c.391G>C has been reported in the literature as a homozygous genotype in multiple reports of individuals with features of chronic hemolysis some of who tested negative for the common deletions in the HBA genes (example, Harkness_1990, Plaseska_1990, Ho_1996, Sarkar_2005, Passarello_2008, Tamaddon_2009, Bayat_2013, Jain_2021). However some of these reports also describe the presence of this variant in cis with other alterations in the HBA2 gene such as a C > T transition in the 5'-untranslated region (UTR) (Sarkar_2005), or HBA2 26 G > A (Hb Caserta) (Passarello_2008, Tamaddon_2009). Variable extent of genotyping results reported make it challenging to determine the role of this variant in isolation. Therefore, these data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23402770, 26523940, 2079430, 8811313, 32199931, 18691171, 2079431, 15813858, 19373587). One clinical diagnostic laboratory and the OMIM database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant in isolation was classified as VUS-possibly pathogenic. -

HEMOGLOBIN SUN PRAIRIE

Other:1

other, no assertion criteria provided

literature only

OMIM

May 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.40

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.15

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

-0.082

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.018

D;D

Vest4

0.76

MutPred

0.85

Loss of stability (P = 0.0652);.;

MVP

1.0

MPC

2.2

ClinPred

0.34

GERP RS

0.64

gMVP

0.93

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over