16-1229340-T-A

Variant names:

• chr16-1229340-T-A
• rs773678304
• NM_024164.6:c.350A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024164.6(TPSB2):​c.350A>T​(p.Gln117Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (1 hom., cov: 5)
  • Exomes 𝑓: 0.000036 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: TPSB2 NM_024164.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.81
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21444035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSB2	NM_024164.6	c.350A>T	p.Gln117Leu	missense_variant	Exon 4 of 6	ENST00000606293.5	NP_077078.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPSB2	ENST00000606293.5	c.350A>T	p.Gln117Leu	missense_variant	Exon 4 of 6	1	NM_024164.6	ENSP00000482743.1

Frequencies

GnomAD3 genomes AF: 0.0000792 AC: 2 AN: 25250 Hom.: 1 Cov.: 5

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000130

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000604 AC: 4 AN: 66190 AF XY: 0.0000869

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000360 AC: 21 AN: 583122 Hom.: 4 Cov.: 7 AF XY: 0.0000269 AC XY: 8 AN XY: 297176

African (AFR) AF: 0.00 AC: 0 AN: 12186

American (AMR) AF: 0.00 AC: 0 AN: 19468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13624

East Asian (EAS) AF: 0.00 AC: 0 AN: 22930

South Asian (SAS) AF: 0.00 AC: 0 AN: 44090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2040

European-Non Finnish (NFE) AF: 0.0000484 AC: 20 AN: 413436

Other (OTH) AF: 0.0000350 AC: 1 AN: 28602

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000792 AC: 2 AN: 25250 Hom.: 1 Cov.: 5 AF XY: 0.000183 AC XY: 2 AN XY: 10904

African (AFR) AF: 0.00 AC: 0 AN: 3596

American (AMR) AF: 0.00 AC: 0 AN: 2846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 650

East Asian (EAS) AF: 0.00 AC: 0 AN: 186

South Asian (SAS) AF: 0.00 AC: 0 AN: 592

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 108

European-Non Finnish (NFE) AF: 0.000130 AC: 2 AN: 15358

Other (OTH) AF: 0.00 AC: 0 AN: 286

Alfa AF: 0.0000743 Hom.: 0

ExAC AF: 0.0000552 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.350A>T (p.Q117L) alteration is located in exon 4 (coding exon 3) of the TPSB2 gene. This alteration results from a A to T substitution at nucleotide position 350, causing the glutamine (Q) at amino acid position 117 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	5.2
DANN	Benign	0.77
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.032	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.53	T
PhyloP100		-1.8
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.27	T;T
Vest4		0.20
MutPred		0.44		Loss of catalytic residue at Q117 (P = 0.061);.;
MVP		0.11
ClinPred		0.61	D
GERP RS		0.72
gMVP		0.33
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs773678304; hg19: chr16-1279341;