Variant rs63751282 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000517.6(HBA2):c.425G>A(p.Arg142His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R142P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.83

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.927

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.425G>A	p.Arg142His	missense_variant	3/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HBA2	ENST00000251595.11 linkuse as main transcript	c.425G>A	p.Arg142His	missense_variant	3/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000482565.1 linkuse as main transcript	n.561G>A		non_coding_transcript_exon_variant	2/2	1
	ENST00000702607.1 linkuse as main transcript	n.65C>T		non_coding_transcript_exon_variant	1/1
HBA2	ENST00000397806.1 linkuse as main transcript	c.329G>A	p.Arg110His	missense_variant	3/3	2		ENSP00000380908

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248848

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459078

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725608

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;T

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.92

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.69

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.2

D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.48

MutPred

0.83

Loss of MoRF binding (P = 7e-04);.;

MVP

0.98

MPC

2.8

ClinPred

0.99

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

gMVP

0.61

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over