Genetic Variant NM_000517.6:c.24G>C (chr16-172936-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PP3_Strong

The NM_000517.6(HBA2):c.24G>C(p.Lys8Asn) variant causes a missense change. 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. K8E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 1)

Exomes 𝑓: 0.0000060 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.91

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 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 6 uncertain in NM_000517.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6 link	c.24G>C	p.Lys8Asn	missense_variant	Exon 1 of 3	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11 link	c.24G>C	p.Lys8Asn	missense_variant	Exon 1 of 3	1	NM_000517.6	ENSP00000251595.6		P69905

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000600

AC:

AN:

333158

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

175862

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8090

American (AMR)

AF:

0.00

AC:

AN:

15076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9992

East Asian (EAS)

AF:

0.00

AC:

AN:

21044

South Asian (SAS)

AF:

0.0000232

AC:

AN:

43056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1352

European-Non Finnish (NFE)

AF:

0.00000509

AC:

AN:

196280

Other (OTH)

AF:

0.00

AC:

AN:

18516

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.94

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.56

PhyloP100

4.9

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.55

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0010

Vest4

0.81

MutPred

0.97

Loss of methylation at K8 (P = 0.0143);

MVP

1.0

MPC

2.4

ClinPred

1.0

GERP RS

1.8

PromoterAI

-0.028

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.95

Mutation Taster

=25/75

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over