16-173590-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_000517.6(HBA2):ā€‹c.419A>Cā€‹(p.Lys140Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K140E) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 25)
Exomes š‘“: 0.0000021 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 missense

Scores

8
6
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.49
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-173589-A-G is described in ClinVar as [Pathogenic, other]. Clinvar id is 15646.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBA2NM_000517.6 linkuse as main transcriptc.419A>C p.Lys140Thr missense_variant 3/3 ENST00000251595.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBA2ENST00000251595.11 linkuse as main transcriptc.419A>C p.Lys140Thr missense_variant 3/31 NM_000517.6 P1
HBA2ENST00000482565.1 linkuse as main transcriptn.555A>C non_coding_transcript_exon_variant 2/21
ENST00000702607.1 linkuse as main transcriptn.71T>G non_coding_transcript_exon_variant 1/1
HBA2ENST00000397806.1 linkuse as main transcriptc.323A>C p.Lys108Thr missense_variant 3/32

Frequencies

GnomAD3 genomes
Cov.:
25
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000206
AC:
3
AN:
1458926
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
725540
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000270
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
0.33
D
BayesDel_noAF
Pathogenic
0.23
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
.;T
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.96
D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.89
D;D
MetaSVM
Pathogenic
0.88
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-5.2
D;D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.017
D;D
Vest4
0.56
MutPred
0.81
Loss of MoRF binding (P = 0.0173);.;
MVP
1.0
MPC
2.7
ClinPred
1.0
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.3
gMVP
0.80

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: rs56348461; hg19: chr16-223589; API