16-1229429-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_024164.6(TPSB2):c.261G>C(p.Arg87Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,183,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 9)

Exomes 𝑓: 0.0018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TPSB2
NM_024164.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.17

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19787222).

BP6

Variant 16-1229429-C-G is Benign according to our data. Variant chr16-1229429-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2338143.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSB2	NM_024164.6 link	c.261G>C	p.Arg87Ser	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.261G>C	p.Arg87Ser	missense_variant	Exon 4 of 6	1	NM_024164.6	ENSP00000482743.1		P20231

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

125

AN:

68376

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000431

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00203

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00303

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00193

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000837

AC:

AN:

66882

AF XY:

0.000960

show subpopulations

Gnomad AFR exome

AF:

0.000426

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.000899

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000838

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00182

AC:

2149

AN:

1183002

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

1037

AN XY:

578828

show subpopulations

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

African (AFR)

AF:

0.000304

AC:

AN:

23048

American (AMR)

AF:

0.00155

AC:

AN:

20688

Ashkenazi Jewish (ASJ)

AF:

0.00176

AC:

AN:

18222

East Asian (EAS)

AF:

0.00

AC:

AN:

32302

South Asian (SAS)

AF:

0.00

AC:

AN:

59612

European-Finnish (FIN)

AF:

0.00246

AC:

AN:

32876

Middle Eastern (MID)

AF:

0.000299

AC:

AN:

3342

European-Non Finnish (NFE)

AF:

0.00200

AC:

1883

AN:

943488

Other (OTH)

AF:

0.00229

AC:

113

AN:

49424

⚠️ 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: 0.342

Heterozygous variant carriers

118

236

355

473

591

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:

0.00183

AC:

125

AN:

68462

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

AN XY:

31490

show subpopulations

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

African (AFR)

AF:

0.000428

AC:

AN:

11690

American (AMR)

AF:

0.00366

AC:

AN:

7110

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

1968

East Asian (EAS)

AF:

0.00

AC:

AN:

1046

South Asian (SAS)

AF:

0.00

AC:

AN:

1464

European-Finnish (FIN)

AF:

0.00303

AC:

AN:

4956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

172

European-Non Finnish (NFE)

AF:

0.00194

AC:

AN:

38758

Other (OTH)

AF:

0.00

AC:

AN:

856

⚠️ 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: 0.387

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000112

Hom.:

ExAC

AF:

0.000359

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 06, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.261G>C (p.R87S) alteration is located in exon 4 (coding exon 3) of the TPSB2 gene. This alteration results from a G to C substitution at nucleotide position 261, causing the arginine (R) at amino acid position 87 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TPSB2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.20

T;T

MetaSVM

Uncertain

-0.18

PhyloP100

1.2

PrimateAI

Uncertain

0.59

Sift4G

Uncertain

0.052

T;D

Vest4

0.53

MutPred

0.67

Loss of methylation at R87 (P = 0.0264);.;

MVP

0.030

ClinPred

0.11

GERP RS

-1.6

gMVP

0.46

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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16-1229429-C-G

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