rs281864844

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BP6

The NM_000517.6(HBA2):c.173G>A(p.Gly58Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 17)

Exomes 𝑓: 0.0000010 ( 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: -1.72

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, 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 1 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 11 uncertain in NM_000517.6

BP6

Variant 16-173202-G-A is Benign according to our data. Variant chr16-173202-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 801171.

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.173G>A	p.Gly58Asp	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.173G>A	p.Gly58Asp	missense	Exon 2 of 3	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1	TSL:1	c.140G>A	p.Gly47Asp	missense	Exon 2 of 2	ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1	TSL:1	n.309G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

116406

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

GnomAD4 exome

AF:

0.00000102

AC:

AN:

983530

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

500950

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

19580

American (AMR)

AF:

0.00

AC:

AN:

35718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22516

East Asian (EAS)

AF:

0.00

AC:

AN:

34128

South Asian (SAS)

AF:

0.00

AC:

AN:

70322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3198

European-Non Finnish (NFE)

AF:

0.00000139

AC:

AN:

719836

Other (OTH)

AF:

0.00

AC:

AN:

44036

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

AF:

0.00

AC:

AN:

116406

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

55732

African (AFR)

AF:

0.00

AC:

AN:

22546

American (AMR)

AF:

0.00

AC:

AN:

12156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3070

East Asian (EAS)

AF:

0.00

AC:

AN:

4140

South Asian (SAS)

AF:

0.00

AC:

AN:

2984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

60176

Other (OTH)

AF:

0.00

AC:

AN:

1526

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 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

0.64

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.013

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.010

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-0.60

PhyloP100

-1.7

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.57

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.053

Vest4

0.50

MutPred

0.48

Loss of ubiquitination at K57 (P = 0.0795)

MVP

1.0

MPC

1.6

ClinPred

0.74

GERP RS

-8.3

PromoterAI

0.013

Neutral

(source)

gMVP

0.85

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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