rs199887053

Positions:

• chr16-1229573-C-G
• chr16-1229573-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024164.6(TPSB2):​c.226G>C​(p.Val76Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,320,564 control chromosomes in the GnomAD database, including 93,140 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (14869 hom., cov: 18)
  • Exomes 𝑓: 0.40 (78271 hom.)
• Consequence: TPSB2 NM_024164.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.62

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.68062E-6).
• BP6: Variant 16-1229573-C-G is Benign according to our data. Variant chr16-1229573-C-G is described in ClinVar as [Benign]. Clinvar id is 403561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPSB2	NM_024164.6	c.226G>C	p.Val76Leu	missense_variant	3/6	ENST00000606293.5	NP_077078.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPSB2	ENST00000606293.5	c.226G>C	p.Val76Leu	missense_variant	3/6	1	NM_024164.6	ENSP00000482743.1
TPSB2	ENST00000612142.1	c.247G>C	p.Val83Leu	missense_variant	2/5	1		ENSP00000478695.1
TPSB2	ENST00000611196.4	n.226G>C		non_coding_transcript_exon_variant	3/8	1		ENSP00000484461.1

Frequencies

GnomAD3 genomes AF: 0.464 AC: 55704 AN: 120138 Hom.: 14862 Cov.: 18

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.371

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.445

GnomAD3 exomes AF: 0.347 AC: 46625 AN: 134232 Hom.: 9178 AF XY: 0.346 AC XY: 25035 AN XY: 72358

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.256

Gnomad ASJ exome AF: 0.269

Gnomad EAS exome AF: 0.594

Gnomad SAS exome AF: 0.273

Gnomad FIN exome AF: 0.520

Gnomad NFE exome AF: 0.345

Gnomad OTH exome AF: 0.325

GnomAD4 exome AF: 0.401 AC: 481570 AN: 1200344 Hom.: 78271 Cov.: 36 AF XY: 0.404 AC XY: 240155 AN XY: 595172

Gnomad4 AFR exome AF: 0.345

Gnomad4 AMR exome AF: 0.332

Gnomad4 ASJ exome AF: 0.400

Gnomad4 EAS exome AF: 0.775

Gnomad4 SAS exome AF: 0.417

Gnomad4 FIN exome AF: 0.608

Gnomad4 NFE exome AF: 0.378

Gnomad4 OTH exome AF: 0.419

GnomAD4 genome AF: 0.464 AC: 55740 AN: 120220 Hom.: 14869 Cov.: 18 AF XY: 0.465 AC XY: 26867 AN XY: 57792

Gnomad4 AFR AF: 0.384

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.434

Gnomad4 EAS AF: 0.789

Gnomad4 SAS AF: 0.450

Gnomad4 FIN AF: 0.631

Gnomad4 NFE AF: 0.478

Gnomad4 OTH AF: 0.443

ExAC AF: 0.350 AC: 40134

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	1.7
DANN	Benign	0.70
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.12	T;T
MetaRNN	Benign	0.0000057	T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.46	T
Sift4G	Benign	0.39	T;T
Vest4		0.046
MutPred		0.66		Gain of catalytic residue at V76 (P = 0.0731);.;
ClinPred		0.0053	T
GERP RS		-4.6
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs199887053; hg19: chr16-1279574; COSMIC: COSV52353496; COSMIC: COSV52353496;