Variant rs33972894 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000517.6(HBA2):c.384G>C(p.Lys128Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,104 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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: 2.44

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:

HBA2 (HGNC:):

HBA2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.384G>C	p.Lys128Asn	missense_variant	3/3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HBA2	ENST00000251595.11 linkuse as main transcript	c.384G>C	p.Lys128Asn	missense_variant	3/3	1	NM_000517.6	ENSP00000251595.6	P69905
HBA2	ENST00000482565.1 linkuse as main transcript	n.520G>C		non_coding_transcript_exon_variant	2/2	1
HBA2	ENST00000397806.1 linkuse as main transcript	c.288G>C	p.Lys96Asn	missense_variant	3/3	2		ENSP00000380908.1	G3V1N2
ENSG00000290038	ENST00000702607.1 linkuse as main transcript	n.106C>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459104

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725626

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.94

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.98

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.72

MutPred

0.77

Loss of methylation at K128 (P = 0.0042);.;

MVP

1.0

MPC

2.7

ClinPred

1.0

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over