Genetic Variant HBA2:p.Pro38Leu (chr16-173142-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000517.6(HBA2):c.113C>T(p.Pro38Leu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P38R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 11)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

other no assertion criteria provided O:1

Conservation

PhyloP100: 5.62

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.113C>T	p.Pro38Leu	missense_variant	Exon 2 of 3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HBA2	ENST00000251595.11 link	c.113C>T	p.Pro38Leu	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1 link	c.80C>T	p.Pro27Leu	missense_variant	Exon 2 of 2	1		ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1 link	n.249C>T		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA2	ENST00000397806.1 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 2 of 3	2		ENSP00000380908.1	G3V1N2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

90854

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000153

AC:

AN:

651600

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

342724

show subpopulations

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:

0.0000165

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

90854

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

42262

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:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000104

AC:

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HEMOGLOBIN MANAWATU

Other:1

Oct 13, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-9.4

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.78

MutPred

0.94

Loss of glycosylation at P38 (P = 0.0535);.;

MVP

1.0

MPC

2.2

ClinPred

1.0

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.97

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