rs281864849

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PP3_ModerateBP6

The NM_000517.6(HBA2):c.193G>A(p.Asp65Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.727

Publications

1 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, ClinGen, 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
unstable hemoglobin disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

HBA2 links:

ENSG00000294455 (HGNC:):

ENSG00000294455 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 14 uncertain in NM_000517.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.887

BP6

Variant 16-173222-G-A is Benign according to our data. Variant chr16-173222-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 994321.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000517.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	NM_000517.6	MANE Select	c.193G>A	p.Asp65Asn	missense	Exon 2 of 3	NP_000508.1	D1MGQ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HBA2	ENST00000251595.11	TSL:1 MANE Select	c.193G>A	p.Asp65Asn	missense	Exon 2 of 3	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1	TSL:1	c.160G>A	p.Asp54Asn	missense	Exon 2 of 2	ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1	TSL:1	n.329G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

124330

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00000755

AC:

AN:

132396

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000944

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000174

AC:

AN:

1148970

Hom.:

Cov.:

AF XY:

0.00000173

AC XY:

AN XY:

576544

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22100

American (AMR)

AF:

0.00

AC:

AN:

35722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23564

East Asian (EAS)

AF:

0.0000288

AC:

AN:

34734

South Asian (SAS)

AF:

0.00

AC:

AN:

73042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3514

European-Non Finnish (NFE)

AF:

0.00000115

AC:

AN:

872676

Other (OTH)

AF:

0.00

AC:

AN:

49464

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

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

AF:

0.00

AC:

AN:

124330

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

59750

African (AFR)

AF:

0.00

AC:

AN:

25254

American (AMR)

AF:

0.00

AC:

AN:

13036

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3214

East Asian (EAS)

AF:

0.00

AC:

AN:

4340

South Asian (SAS)

AF:

0.00

AC:

AN:

3354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63170

Other (OTH)

AF:

0.00

AC:

AN:

1656

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0087

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.041

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.89

MetaSVM

Uncertain

-0.26

PhyloP100

0.73

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.32

Sift

Benign

0.054

Sift4G

Benign

0.66

Vest4

0.56

MutPred

0.91

Gain of MoRF binding (P = 0.0491)

MVP

1.0

MPC

1.3

ClinPred

0.059

GERP RS

4.2

PromoterAI

-0.0058

Neutral

(source)

gMVP

0.80

Mutation Taster

=17/83

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over