16-1256632-G-C

Position:

• chr16-1256632-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000211076.5(TPSD1):​c.199G>C​(p.Gly67Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,584 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: 37)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TPSD1 ENST00000211076.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.461

Genes affected

TPSD1 (HGNC:14118): (tryptase delta 1) 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. Although this gene may be an exception, most of the tryptase 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. Tryptases have been implicated as mediators in the pathogenesis of asthma and other allergic and inflammatory disorders. This gene was once considered to be a pseudogene, although it is now believed to be a functional gene that encodes a protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPSD1	NM_012217.3	c.199G>C	p.Gly67Arg	missense_variant	2/5	ENST00000211076.5	NP_036349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPSD1	ENST00000211076.5	c.199G>C	p.Gly67Arg	missense_variant	2/5	1	NM_012217.3	ENSP00000211076.3
TPSD1	ENST00000397534.6	c.178G>C	p.Gly60Arg	missense_variant	3/6	5		ENSP00000380668.2

Frequencies

GnomAD3 genomes Cov.: 37

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460584 Hom.: 0 Cov.: 120 AF XY: 0.00000138 AC XY: 1 AN XY: 726612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 37

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.199G>C (p.G67R) alteration is located in exon 2 (coding exon 2) of the TPSD1 gene. This alteration results from a G to C substitution at nucleotide position 199, causing the glycine (G) at amino acid position 67 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
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	.;D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.6	.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.028	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		1.0	.;D
Vest4		0.36
MutPred		0.94		.;Gain of MoRF binding (P = 0.0106);
MVP		0.79
MPC		0.059
ClinPred		0.99	D
GERP RS		0.90
Varity_R		0.83
gMVP		0.80

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-1306633;