Genetic Variant TPSB2:p.Ala120Val (chr16-1229331-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024164.6(TPSB2):c.359C>T(p.Ala120Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000093 ( 0 hom., cov: 4)

Exomes 𝑓: 0.0017 ( 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: -0.144

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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0455395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSB2	NM_024164.6 link	c.359C>T	p.Ala120Val	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.359C>T	p.Ala120Val	missense_variant	Exon 4 of 6	1	NM_024164.6	ENSP00000482743.1		P20231

Frequencies

GnomAD3 genomes

AF:

0.0000927

AC:

AN:

21584

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000412

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:

0.0000753

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00335

AC:

215

AN:

64122

AF XY:

0.00320

show subpopulations

Gnomad AFR exome

AF:

0.000680

Gnomad AMR exome

AF:

0.00393

Gnomad ASJ exome

AF:

0.00424

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00125

Gnomad NFE exome

AF:

0.00436

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00169

AC:

921

AN:

545332

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

450

AN XY:

277938

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000343

AC:

AN:

11648

American (AMR)

AF:

0.00103

AC:

AN:

18486

Ashkenazi Jewish (ASJ)

AF:

0.00176

AC:

AN:

13068

East Asian (EAS)

AF:

0.00

AC:

AN:

19880

South Asian (SAS)

AF:

0.000886

AC:

AN:

41742

European-Finnish (FIN)

AF:

0.00415

AC:

102

AN:

24592

Middle Eastern (MID)

AF:

0.00517

AC:

AN:

1934

European-Non Finnish (NFE)

AF:

0.00171

AC:

663

AN:

387014

Other (OTH)

AF:

0.00234

AC:

AN:

26968

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.394

Heterozygous variant carriers

135

180

225

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:

0.0000926

AC:

AN:

21588

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

9332

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

2968

American (AMR)

AF:

0.000411

AC:

AN:

2434

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

560

East Asian (EAS)

AF:

0.00

AC:

AN:

144

South Asian (SAS)

AF:

0.00

AC:

AN:

554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000753

AC:

AN:

13278

Other (OTH)

AF:

0.00

AC:

AN:

258

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00156

Hom.:

ExAC

AF:

0.000199

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 19, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.359C>T (p.A120V) alteration is located in exon 4 (coding exon 3) of the TPSB2 gene. This alteration results from a C to T substitution at nucleotide position 359, causing the alanine (A) at amino acid position 120 to be replaced by a valine (V). 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

Uncertain

0.075

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.73

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.046

T;T

MetaSVM

Benign

-0.59

PhyloP100

-0.14

PrimateAI

Benign

0.31

Sift4G

Uncertain

0.035

D;D

Vest4

0.34

MutPred

0.60

Loss of stability (P = 0.1194);.;

MVP

0.18

ClinPred

0.053

GERP RS

-1.2

gMVP

0.25

Mutation Taster

=94/6

polymorphism

(source)

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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16-1229331-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over