16-1229669-A-G

Variant names:

• chr16-1229669-A-G
• rs1420405720
• NM_024164.6:c.130T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024164.6(TPSB2):​c.130T>C​(p.Trp44Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TPSB2 NM_024164.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSB2	NM_024164.6	c.130T>C	p.Trp44Arg	missense_variant	Exon 3 of 6	ENST00000606293.5	NP_077078.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPSB2	ENST00000606293.5	c.130T>C	p.Trp44Arg	missense_variant	Exon 3 of 6	1	NM_024164.6	ENSP00000482743.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458528 Hom.: 0 Cov.: 90 AF XY: 0.00 AC XY: 0 AN XY: 725528

African (AFR) AF: 0.00 AC: 0 AN: 32906

American (AMR) AF: 0.00 AC: 0 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 85808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5124

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111520

Other (OTH) AF: 0.0000166 AC: 1 AN: 60190

GnomAD4 genome Cov.: 28

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.130T>C (p.W44R) alteration is located in exon 3 (coding exon 2) of the TPSB2 gene. This alteration results from a T to C substitution at nucleotide position 130, causing the tryptophan (W) at amino acid position 44 to be replaced by an arginine (R). 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	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	0.34	D
PhyloP100		3.1
PrimateAI	Uncertain	0.74	T
Sift4G	Pathogenic	0.0	D;D
Vest4		0.83
MutPred		0.86		Gain of disorder (P = 0.0056);.;
MVP		0.50
ClinPred		1.0	D
GERP RS		4.0
PromoterAI		-0.013	Neutral
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1420405720; hg19: chr16-1279670;