Genetic Variant TPSB2:p.Ala239Glu (chr16-1228762-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024164.6(TPSB2):c.716C>A(p.Ala239Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000764 in 1,438,886 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A239V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 18)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Consequence

TPSB2
NM_024164.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0720

Publications

2 publications found

Variant links:

Genes affected

TPSB2 (HGNC:14120): (tryptase beta 2) Tryptases comprise a family of trypsin-like serine proteases, the peptidase family S1. Tryptases are enzymatically active only as heparin-stabilized tetramers, and they are resistant to all known endogenous proteinase inhibitors. Several tryptase genes are clustered on chromosome 16p13.3. These genes are characterized by several distinct features. They have a highly conserved 3' UTR and contain tandem repeat sequences at the 5' flank and 3' UTR which are thought to play a role in regulation of the mRNA stability. These genes have an intron immediately upstream of the initiator Met codon, which separates the site of transcription initiation from protein coding sequence. This feature is characteristic of tryptases but is unusual in other genes. The alleles of this gene exhibit an unusual amount of sequence variation, such that the alleles were once thought to represent two separate genes, beta II and beta III. Beta tryptases appear to be the main isoenzymes expressed in mast cells, whereas in basophils, alpha-tryptases predominate. Tryptases have been implicated as mediators in the pathogenesis of asthma and other allergic and inflammatory disorders. [provided by RefSeq, Jul 2008]

TPSB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSB2	NM_024164.6 link	c.716C>A	p.Ala239Glu	missense_variant	Exon 6 of 6	ENST00000606293.5	NP_077078.5	P20231A0A140VJT7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPSB2	ENST00000606293.5 link	c.716C>A	p.Ala239Glu	missense_variant	Exon 6 of 6	1	NM_024164.6	ENSP00000482743.1		P20231

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000435

AC:

AN:

230022

AF XY:

0.00000798

show subpopulations

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:

0.00000974

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000764

AC:

AN:

1438886

Hom.:

Cov.:

AF XY:

0.0000126

AC XY:

AN XY:

713972

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32300

American (AMR)

AF:

0.00

AC:

AN:

43258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25376

East Asian (EAS)

AF:

0.00

AC:

AN:

38494

South Asian (SAS)

AF:

0.00

AC:

AN:

84662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4890

European-Non Finnish (NFE)

AF:

0.0000100

AC:

AN:

1098408

Other (OTH)

AF:

0.00

AC:

AN:

59272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000249

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.022

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

-0.033

PhyloP100

0.072

PrimateAI

Benign

0.43

Sift4G

Uncertain

0.010

D;D

Vest4

0.62

MutPred

0.73

Loss of catalytic residue at S243 (P = 0.155);.;

MVP

0.15

ClinPred

0.98

GERP RS

1.8

gMVP

0.59

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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16-1228762-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over