chr16-1229569-C-T

Variant names:

• chr16-1229569-C-T
• rs557145756
• NM_024164.6:c.230G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024164.6(TPSB2):​c.230G>A​(p.Gly77Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,525,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 18)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TPSB2 NM_024164.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.133
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17342821).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSB2	NM_024164.6	c.230G>A	p.Gly77Glu	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.230G>A	p.Gly77Glu	missense_variant	Exon 3 of 6	1	NM_024164.6	ENSP00000482743.1

Frequencies

GnomAD3 genomes AF: 0.0000155 AC: 2 AN: 129294 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.0000327

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: 0.0000157

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000561 AC: 1 AN: 178232 AF XY: 0.0000103

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: 0.0000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000143 AC: 20 AN: 1396210 Hom.: 0 Cov.: 33 AF XY: 0.0000174 AC XY: 12 AN XY: 690522

African (AFR) AF: 0.00 AC: 0 AN: 29536

American (AMR) AF: 0.0000288 AC: 1 AN: 34750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22202

East Asian (EAS) AF: 0.00 AC: 0 AN: 36980

South Asian (SAS) AF: 0.0000407 AC: 3 AN: 73746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4294

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1087930

Other (OTH) AF: 0.0000348 AC: 2 AN: 57456

GnomAD4 genome AF: 0.0000155 AC: 2 AN: 129382 Hom.: 0 Cov.: 18 AF XY: 0.0000321 AC XY: 2 AN XY: 62386

African (AFR) AF: 0.0000326 AC: 1 AN: 30656

American (AMR) AF: 0.00 AC: 0 AN: 13268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3302

East Asian (EAS) AF: 0.00 AC: 0 AN: 3004

South Asian (SAS) AF: 0.00 AC: 0 AN: 3650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.0000157 AC: 1 AN: 63580

Other (OTH) AF: 0.00 AC: 0 AN: 1764

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.00000836 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.230G>A (p.G77E) alteration is located in exon 3 (coding exon 2) of the TPSB2 gene. This alteration results from a G to A substitution at nucleotide position 230, causing the glycine (G) at amino acid position 77 to be replaced by a glutamic acid (E). 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	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Benign	0.72
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.075	T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.51	T
PhyloP100		0.13
PrimateAI	Uncertain	0.60	T
Sift4G	Benign	0.50	T;T
Vest4		0.41
MutPred		0.36		Gain of disorder (P = 0.2511);.;
MVP		0.29
ClinPred		0.42	T
GERP RS		2.5
gMVP		0.45
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs557145756; hg19: chr16-1279570;