NM_000517.6:c.142G>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PP3_ModeratePP5_Very_Strong

The NM_000517.6(HBA2):c.142G>C(p.Asp48His) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D48Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 12)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:4

Conservation

PhyloP100: 5.34

Publications

2 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: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 11 uncertain in NM_000517.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

PP5

Variant 16-173171-G-C is Pathogenic according to our data. Variant chr16-173171-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 15636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.142G>C	p.Asp48His	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.142G>C	p.Asp48His	missense	Exon 2 of 3	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1	TSL:1	c.109G>C	p.Asp37His	missense	Exon 2 of 2	ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1	TSL:1	n.278G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000401

AC:

AN:

99842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00143

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:

0.0000945

AC:

AN:

126964

AF XY:

0.0000438

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00161

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000254

GnomAD4 exome

AF:

0.0000416

AC:

AN:

793608

Hom.:

Cov.:

AF XY:

0.0000243

AC XY:

AN XY:

411868

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17340

American (AMR)

AF:

0.00

AC:

AN:

36092

Ashkenazi Jewish (ASJ)

AF:

0.00114

AC:

AN:

21082

East Asian (EAS)

AF:

0.00

AC:

AN:

33606

South Asian (SAS)

AF:

0.00

AC:

AN:

66624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34524

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2848

European-Non Finnish (NFE)

AF:

0.00000736

AC:

AN:

543748

Other (OTH)

AF:

0.000132

AC:

AN:

37744

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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

AF:

0.0000401

AC:

AN:

99842

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

46988

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17818

American (AMR)

AF:

0.00

AC:

AN:

10236

Ashkenazi Jewish (ASJ)

AF:

0.00143

AC:

AN:

2792

East Asian (EAS)

AF:

0.00

AC:

AN:

3720

South Asian (SAS)

AF:

0.00

AC:

AN:

2312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53556

Other (OTH)

AF:

0.00

AC:

AN:

1230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000240

Hom.:

ExAC

AF:

0.0000402

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

alpha Thalassemia (2)

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7 (1)

HEMOGLOBIN HASHARON (1)

HEMOGLOBIN L (FERRARA) (1)

HEMOGLOBIN SEALY (1)

HEMOGLOBIN SINAI (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.050

Eigen

Benign

0.18

Eigen_PC

Benign

0.10

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.59

PhyloP100

5.3

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Vest4

0.62

MutPred

0.96

Gain of disorder (P = 0.1421)

MVP

1.0

MPC

1.9

ClinPred

0.67

GERP RS

3.2

PromoterAI

-0.046

Neutral

(source)

gMVP

0.88

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over