chr16-173502-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000517.6(HBA2):​c.331G>A​(p.Ala111Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 25)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HBA2
NM_000517.6 missense

Scores

8
6
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.54
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HBA2NM_000517.6 linkuse as main transcriptc.331G>A p.Ala111Thr missense_variant 3/3 ENST00000251595.11 NP_000508.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HBA2ENST00000251595.11 linkuse as main transcriptc.331G>A p.Ala111Thr missense_variant 3/31 NM_000517.6 ENSP00000251595 P1
ENST00000702607.1 linkuse as main transcriptn.159C>T non_coding_transcript_exon_variant 1/1

Frequencies

GnomAD3 genomes
Cov.:
25
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1458448
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
725328
show subpopulations
Gnomad4 AFR exome
AF:
0.0000315
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.20
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
.;T
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.88
D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Pathogenic
0.97
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-3.6
D;D
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Vest4
0.52
MutPred
0.76
Gain of glycosylation at A111 (P = 0.1656);.;
MVP
1.0
MPC
2.4
ClinPred
1.0
D
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
gMVP
0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs281864883; hg19: chr16-223501; API