Genetic Variant NM_024164.6:c.367G>C (chr16-1229323-C-G) – 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>C(p.Ala123Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. A123T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 3)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

TPSB2
NM_024164.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.77

Publications

0 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSB2	NM_024164.6 link	c.367G>C	p.Ala123Pro	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>C	p.Ala123Pro	missense_variant	Exon 4 of 6	1	NM_024164.6	ENSP00000482743.1		P20231

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000193

AC:

AN:

517880

Hom.:

Cov.:

AF XY:

0.00000378

AC XY:

AN XY:

264640

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11362

American (AMR)

AF:

0.00

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:

0.00

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:

0.00000274

AC:

AN:

364828

Other (OTH)

AF:

0.00

AC:

AN:

26084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.090

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.28

PhyloP100

1.8

PrimateAI

Benign

0.43

Sift4G

Uncertain

0.0030

D;D

Vest4

0.75

MutPred

0.87

Loss of stability (P = 0.0578);.;

MVP

0.12

ClinPred

0.99

GERP RS

2.6

gMVP

0.84

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over