chr16-172950-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PP3_StrongBP6

The NM_000517.6(HBA2):c.38C>A(p.Ala13Asp) 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: not found (cov: 1)

Exomes 𝑓: 0.000019 ( 1 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.164

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 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 8 uncertain in NM_000517.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.975

BP6

Variant 16-172950-C-A is Benign according to our data. Variant chr16-172950-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 993109.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.38C>A	p.Ala13Asp	missense_variant	Exon 1 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11 link	c.38C>A	p.Ala13Asp	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

53250

AF XY:

0.00

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:

0.0000190

AC:

AN:

368084

Hom.:

Cov.:

AF XY:

0.0000310

AC XY:

AN XY:

193584

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8872

American (AMR)

AF:

0.00

AC:

AN:

16142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11266

East Asian (EAS)

AF:

0.00

AC:

AN:

24174

South Asian (SAS)

AF:

0.000161

AC:

AN:

43562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22938

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1562

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

218702

Other (OTH)

AF:

0.00

AC:

AN:

20866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.585

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

Cov.:

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

Apr 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Hb-J-Paris-I variant (HBA2: c.38C>A; p.Ala13Asp, also known as Ala12Asp when numbered from the mature protein, rs281864809, HbVar ID: 15) is reported in the literature in individuals with no clinical symptoms or hematological alterations, and is described as a stable hemoglobin variant (see link to HbVar and references therein, de la Fuente-Gonzalo 2019, Kimura 2015, Molchanova 1994). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 13 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.558). Based on available information, this variant is considered to be likely benign. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html de la Fuente-Gonzalo F et al. Characterization of deletional and non-deletional alpha globin variants in a large cohort from Spain between 2009 and 2014. Ann Hematol. 2019 Jul;98(7):1537-1545. PMID: 31025160. Kimura EM et al. Investigating alpha-globin structural variants: a retrospective review of 135,000 Brazilian individuals. Rev Bras Hematol Hemoter. 2015 Mar-Apr;37(2):103-8. PMID: 25818820. Molchanova TP et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994 Oct;88(2):300-6. PMID: 7803274. -

Sep 05, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBA2 c.38C>A (p.Ala13Asp) variant has been reported in the published literature in individuals with hematological indices and clinical phenotypes within normal range (PMID: 32597250 (2020), 31025160 (2019), 30489691 (2018), 27387985 (2017), 25818820 (2015), and 119167 (1979)). In an online hemoglobin database, this variant is reported as stable (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

(source)

DANN

Benign

0.91

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.065

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

-0.084

PhyloP100

0.16

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.56

Sift

Uncertain

0.010

Sift4G

Benign

0.077

Vest4

0.77

MutPred

0.95

Loss of MoRF binding (P = 0.0276);

MVP

1.0

MPC

1.8

ClinPred

0.26

GERP RS

1.5

PromoterAI

-0.039

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.75

Mutation Taster

=15/85

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over