16-1229293-C-T

Position:

• chr16-1229293-C-T

Variant summary

Our verdict is Likely benign. Variant got -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. 10/16 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.24

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]

ACMG classification

Verdict is Likely_benign. Variant got -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/exons	MANE	UniProt
TPSB2	NM_024164.6	c.397G>A	p.Val133Ile	missense_variant	4/6	ENST00000606293.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPSB2	ENST00000606293.5	c.397G>A	p.Val133Ile	missense_variant	4/6	1	NM_024164.6	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 162 AN: 10636 Hom.: 0 Cov.: 1 FAILED QC

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

GnomAD3 exomes AF: 0.102 AC: 5566 AN: 54702 Hom.: 88 AF XY: 0.103 AC XY: 2976 AN XY: 28822

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 SAS exome AF: 0.147

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.: 5 AF XY: 0.157 AC XY: 26361 AN XY: 167480

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.397

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.246

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.168

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0151 AC: 161 AN: 10638 Hom.: 0 Cov.: 1 AF XY: 0.0154 AC XY: 70 AN XY: 4554

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.0153

Gnomad4 ASJ AF: 0.00694

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.0679

Gnomad4 FIN AF: 0.00543

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.0278

Alfa AF: 0.132 Hom.: 21

ExAC AF: 0.00135 AC: 41

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

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	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.0050
DANN	Benign	0.77
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.054	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.38	T;T
Vest4		0.052
ClinPred		0.011	T
GERP RS		-6.7
gMVP		0.10

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

LitVar

Other links and lift over

dbSNP: rs779125655; hg19: chr16-1279294;