Genetic Variant TPSB2:p.Ala123Thr (chr16-1229323-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_024164.6(TPSB2):c.367G>A(p.Ala123Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., cov: 3)

Exomes 𝑓: 0.000031 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TPSB2
NM_024164.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSB2	NM_024164.6 link	c.367G>A	p.Ala123Thr	missense_variant	Exon 4 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.367G>A	p.Ala123Thr	missense_variant	Exon 4 of 6	1	NM_024164.6	ENSP00000482743.1		P20231

Frequencies

GnomAD3 genomes

AF:

0.0000559

AC:

AN:

17876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000893

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

62090

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000309

AC:

AN:

517878

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

264638

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11362

American (AMR)

AF:

0.0000552

AC:

AN:

18114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12908

East Asian (EAS)

AF:

0.00

AC:

AN:

17360

South Asian (SAS)

AF:

0.0000719

AC:

AN:

41732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1918

European-Non Finnish (NFE)

AF:

0.0000329

AC:

AN:

364826

Other (OTH)

AF:

0.00

AC:

AN:

26084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.591

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000559

AC:

AN:

17876

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

7636

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

2290

American (AMR)

AF:

0.00

AC:

AN:

2038

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

488

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000893

AC:

AN:

11194

Other (OTH)

AF:

0.00

AC:

AN:

226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.000147

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.367G>A (p.A123T) alteration is located in exon 4 (coding exon 3) of the TPSB2 gene. This alteration results from a G to A substitution at nucleotide position 367, causing the alanine (A) at amino acid position 123 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.14

PhyloP100

1.8

PrimateAI

Benign

0.39

Sift4G

Uncertain

0.024

D;D

Vest4

0.49

MutPred

0.89

Loss of stability (P = 0.1208);.;

MVP

0.081

ClinPred

0.99

GERP RS

2.6

gMVP

0.58

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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16-1229323-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over