rs281864827

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM5PP3_Strong

The NM_000517.6(HBA2):​c.121A>C​(p.Lys41Gln) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. K41M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 11)

Consequence

HBA2
NM_000517.6 missense

Scores

5
8
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.80
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 Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000517.6
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-173151-A-T is described in ClinVar as [Pathogenic, other]. Clinvar id is 15844.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBA2NM_000517.6 linkuse as main transcriptc.121A>C p.Lys41Gln missense_variant 2/3 ENST00000251595.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBA2ENST00000251595.11 linkuse as main transcriptc.121A>C p.Lys41Gln missense_variant 2/31 NM_000517.6 P1
HBA2ENST00000484216.1 linkuse as main transcriptc.91A>C p.Lys31Gln missense_variant 2/21
HBA2ENST00000482565.1 linkuse as main transcriptn.257A>C non_coding_transcript_exon_variant 1/21
HBA2ENST00000397806.1 linkuse as main transcriptc.25A>C p.Lys9Gln missense_variant 2/32

Frequencies

GnomAD3 genomes
Cov.:
11
GnomAD4 exome
Cov.:
9
GnomAD4 genome
Cov.:
11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.039
.;T
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
0.57
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.79
T
PROVEAN
Uncertain
-3.9
D;D
REVEL
Pathogenic
0.81
Sift
Pathogenic
0.0
D;D
Sift4G
Benign
0.094
T;T
Vest4
0.71
MutPred
0.89
Loss of methylation at K41 (P = 0.0059);.;
MVP
1.0
MPC
2.6
ClinPred
0.99
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
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: rs281864827; hg19: chr16-223149; API