16-1228762-G-A

Position:

• chr16-1228762-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_024164.6(TPSB2):​c.716C>T​(p.Ala239Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,569,138 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 18)
  • Exomes 𝑓: 0.0023 (16 hom.)
• Consequence: TPSB2 NM_024164.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0720

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0325495).
• BP6: Variant 16-1228762-G-A is Benign according to our data. Variant chr16-1228762-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2645884.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPSB2	NM_024164.6	c.716C>T	p.Ala239Val	missense_variant	6/6	ENST00000606293.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPSB2	ENST00000606293.5	c.716C>T	p.Ala239Val	missense_variant	6/6	1	NM_024164.6	P2

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 193 AN: 130472 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.000590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00115

Gnomad ASJ AF: 0.000618

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000550

Gnomad FIN AF: 0.000434

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00187 AC: 430 AN: 230022 Hom.: 8 AF XY: 0.00218 AC XY: 273 AN XY: 125274

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000730

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00443

Gnomad FIN exome AF: 0.000736

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00225 AC: 3244 AN: 1438590 Hom.: 16 Cov.: 34 AF XY: 0.00233 AC XY: 1661 AN XY: 713758

Gnomad4 AFR exome AF: 0.000465

Gnomad4 AMR exome AF: 0.000740

Gnomad4 ASJ exome AF: 0.000236

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.00430

Gnomad4 FIN exome AF: 0.000823

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00148 AC: 193 AN: 130548 Hom.: 0 Cov.: 18 AF XY: 0.00137 AC XY: 86 AN XY: 62684

Gnomad4 AFR AF: 0.000588

Gnomad4 AMR AF: 0.00115

Gnomad4 ASJ AF: 0.000618

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000551

Gnomad4 FIN AF: 0.000434

Gnomad4 NFE AF: 0.00243

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00186 Hom.: 0

ESP6500AA AF: 0.000696 AC: 3

ESP6500EA AF: 0.00247 AC: 21

ExAC AF: 0.00181 AC: 218

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

TPSB2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	11
DANN	Benign	0.71
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.63	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
Sift4G	Benign	1.0	T;T
Vest4		0.17
MVP		0.072
ClinPred		0.021	T
GERP RS		1.8
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs377518279; hg19: chr16-1278762;