16-173206-C-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM5PP3_Strong

The NM_000517.6(HBA2):c.177C>G(p.His59Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H59Y) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 18)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.13

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, 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

HBA2 links:

ENSG00000294455 (HGNC:):

ENSG00000294455 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-173204-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3346945.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	NM_000517.6	MANE Select	c.177C>G	p.His59Gln	missense	Exon 2 of 3	NP_000508.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HBA2	ENST00000251595.11	TSL:1 MANE Select	c.177C>G	p.His59Gln	missense	Exon 2 of 3	ENSP00000251595.6
HBA2	ENST00000484216.1	TSL:1	c.144C>G	p.His48Gln	missense	Exon 2 of 2	ENSP00000495899.1
HBA2	ENST00000482565.1	TSL:1	n.313C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

119058

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:

0.00000763

AC:

AN:

131066

AF XY:

0.0000141

show subpopulations

Gnomad AFR exome

AF:

0.000157

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000295

AC:

AN:

1017334

Hom.:

Cov.:

AF XY:

0.00000387

AC XY:

AN XY:

516444

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

20144

American (AMR)

AF:

0.00

AC:

AN:

35706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22738

East Asian (EAS)

AF:

0.00

AC:

AN:

34256

South Asian (SAS)

AF:

0.00

AC:

AN:

70840

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3262

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

751220

Other (OTH)

AF:

0.00

AC:

AN:

45022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

119058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

57186

African (AFR)

AF:

0.00

AC:

AN:

23274

American (AMR)

AF:

0.00

AC:

AN:

12484

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3118

East Asian (EAS)

AF:

0.00

AC:

AN:

4192

South Asian (SAS)

AF:

0.00

AC:

AN:

3108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61236

Other (OTH)

AF:

0.00

AC:

AN:

1566

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

7.6

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.11

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.094

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.39

PhyloP100

-5.1

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.0

REVEL

Uncertain

0.60

Sift

Benign

0.12

Sift4G

Uncertain

0.051

Vest4

0.58

MutPred

0.95

Loss of ubiquitination at K57 (P = 0.1113)

MVP

1.0

MPC

1.8

ClinPred

0.48

GERP RS

-8.3

PromoterAI

-0.0062

Neutral

(source)

gMVP

0.97

Mutation Taster

=5/95

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