Genetic Variant HBA2:p.Pro115Ala (chr16-173514-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_000517.6(HBA2):c.343C>G(p.Pro115Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,618 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P115L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.85

Publications

0 publications found

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 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

HBA2 links:

ENSG00000294455 (HGNC:):

ENSG00000294455 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 uncertain in NM_000517.6

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.343C>G	p.Pro115Ala	missense_variant	Exon 3 of 3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11 link	c.343C>G	p.Pro115Ala	missense_variant	Exon 3 of 3	1	NM_000517.6	ENSP00000251595.6		P69905

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458618

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725388

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31892

American (AMR)

AF:

0.00

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

85140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111842

Other (OTH)

AF:

0.0000166

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.13

.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.11

M_CAP

Pathogenic

0.57

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Uncertain

0.24

PhyloP100

1.8

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.019

D;D

Sift4G

Uncertain

0.048

D;T

Vest4

0.28

MutPred

0.53

Loss of phosphorylation at T119 (P = 0.1932);.;

MVP

0.97

MPC

1.2

ClinPred

0.88

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

gMVP

0.83

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

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16-173514-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over