16-1229293-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_024164.6(TPSB2):c.397G>A(p.Val133Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.015 ( 0 hom., cov: 1)

Exomes 𝑓: 0.16 ( 183 hom. )

Failed GnomAD Quality Control

Consequence

TPSB2
NM_024164.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.24

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 -2 ACMG points.

BP6

Variant 16-1229293-C-T is Benign according to our data. Variant chr16-1229293-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2409465.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSB2	NM_024164.6 link	c.397G>A	p.Val133Ile	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.397G>A	p.Val133Ile	missense_variant	Exon 4 of 6	1	NM_024164.6	ENSP00000482743.1		P20231

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

162

AN:

10636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0207

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0162

Gnomad ASJ

AF:

0.00694

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.0704

Gnomad FIN

AF:

0.00543

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0123

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.102

AC:

5566

AN:

54702

AF XY:

0.103

show subpopulations

Gnomad AFR exome

AF:

0.141

Gnomad AMR exome

AF:

0.102

Gnomad ASJ exome

AF:

0.0542

Gnomad EAS exome

AF:

0.427

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.0715

Gnomad OTH exome

AF:

0.110

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.156

AC:

50493

AN:

324710

Hom.:

183

Cov.:

AF XY:

0.157

AC XY:

26361

AN XY:

167480

show subpopulations

African (AFR)

AF:

0.164

AC:

1321

AN:

8070

American (AMR)

AF:

0.142

AC:

1779

AN:

12486

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

1323

AN:

8652

East Asian (EAS)

AF:

0.397

AC:

4994

AN:

12568

South Asian (SAS)

AF:

0.204

AC:

5945

AN:

29096

European-Finnish (FIN)

AF:

0.246

AC:

3801

AN:

15460

Middle Eastern (MID)

AF:

0.141

AC:

178

AN:

1264

European-Non Finnish (NFE)

AF:

0.129

AC:

28309

AN:

220194

Other (OTH)

AF:

0.168

AC:

2843

AN:

16920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

2085

4170

6256

8341

10426

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:

0.0151

AC:

161

AN:

10638

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

AN XY:

4554

show subpopulations

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

African (AFR)

AF:

0.0214

AC:

AN:

1214

American (AMR)

AF:

0.0153

AC:

AN:

1240

Ashkenazi Jewish (ASJ)

AF:

0.00694

AC:

AN:

288

East Asian (EAS)

AF:

0.109

AC:

AN:

South Asian (SAS)

AF:

0.0679

AC:

AN:

280

European-Finnish (FIN)

AF:

0.00543

AC:

AN:

552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0123

AC:

AN:

6750

Other (OTH)

AF:

0.0278

AC:

AN:

144

⚠️ 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: 0.276

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.132

Hom.:

ExAC

AF:

0.00135

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 22, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.0050

(source)

DANN

Benign

0.77

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.054

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-0.89

PhyloP100

-2.2

PrimateAI

Benign

0.29

Sift4G

Benign

0.38

T;T

Vest4

0.052

ClinPred

0.011

GERP RS

-6.7

gMVP

0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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16-1229293-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