16-172976-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP3BP6

The NM_000517.6(HBA2):c.64G>C(p.Ala22Pro) 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: 2)

Exomes 𝑓: 0.000022 ( 1 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: 0.550

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: Uncertain_significance. The variant received 2 ACMG points.

PM1

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

BP6

Variant 16-172976-G-C is Benign according to our data. Variant chr16-172976-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 801178.

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.64G>C	p.Ala22Pro	missense	Exon 1 of 3	NP_000508.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HBA2	ENST00000251595.11	TSL:1 MANE Select	c.64G>C	p.Ala22Pro	missense	Exon 1 of 3	ENSP00000251595.6
HBA2	ENST00000484216.1	TSL:1	c.31G>C	p.Ala11Pro	missense	Exon 1 of 2	ENSP00000495899.1
HBA2	ENST00000482565.1	TSL:1	n.83G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

4754

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:

0.0000188

AC:

AN:

53330

AF XY:

0.0000372

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

411840

Hom.:

Cov.:

AF XY:

0.0000323

AC XY:

AN XY:

216496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

10010

American (AMR)

AF:

0.00

AC:

AN:

17684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12684

East Asian (EAS)

AF:

0.00

AC:

AN:

28100

South Asian (SAS)

AF:

0.000158

AC:

AN:

44180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26802

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1778

European-Non Finnish (NFE)

AF:

0.00000405

AC:

AN:

247048

Other (OTH)

AF:

0.0000425

AC:

AN:

23554

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

4724

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

2328

African (AFR)

AF:

0.00

AC:

AN:

674

American (AMR)

AF:

0.00

AC:

AN:

788

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

548

South Asian (SAS)

AF:

0.00

AC:

AN:

514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1854

Other (OTH)

AF:

0.00

AC:

AN:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Dec 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HB2 c.64G>C (p.Ala22Pro), also known as Hb Fontainebleau, variant is reported as having normal stability (see HbVar, http://globin.bx.psu.edu/cgi-bin/hbvar/counter, PMID: 2599878 (2009)). This variant has been observed in a screening study of alpha thalassemia carriers (PMID: 29627922 (2018)). It has also been detected in an individual with suspected hemoglobinopathy (PMID: 38708170 (2024)). The variant has been reported in homozygous and compound heterozygous individuals with microcytosis (PMID: 22461654 (2012), 24826794 (2014), 26036869 (2015), and 30728682 (2019)) as well as in individuals with normal red cell indices (PMID: 19657841 (2009)). Based on the available information, we are unable to determine the clinical significance of this variant.

Mar 23, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.11

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

-0.098

PhyloP100

0.55

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.57

Sift

Uncertain

0.014

Sift4G

Uncertain

0.056

Vest4

0.22

MutPred

0.83

Gain of methylation at K17 (P = 0.0559)

MVP

1.0

MPC

1.7

ClinPred

0.085

GERP RS

3.0

PromoterAI

-0.017

Neutral

(source)

gMVP

0.95

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over