16-1256677-T-A

Position:

• chr16-1256677-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_012217.3(TPSD1):​c.244T>A​(p.Cys82Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,766 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: 38)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TPSD1 NM_012217.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.693

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPSD1	NM_012217.3	c.244T>A	p.Cys82Ser	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.244T>A	p.Cys82Ser	missense_variant	2/5	1	NM_012217.3	ENSP00000211076.3
TPSD1	ENST00000397534.6	c.223T>A	p.Cys75Ser	missense_variant	3/6	5		ENSP00000380668.2

Frequencies

GnomAD3 genomes Cov.: 38

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458766 Hom.: 0 Cov.: 133 AF XY: 0.00000138 AC XY: 1 AN XY: 725496

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 38

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

Apr 09, 2024

The c.244T>A (p.C82S) alteration is located in exon 2 (coding exon 2) of the TPSD1 gene. This alteration results from a T to A substitution at nucleotide position 244, causing the cysteine (C) at amino acid position 82 to be replaced by a serine (S). 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	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	.;D
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.043
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.5	.;H
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-9.4	D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.72
MutPred		0.88		.;Gain of disorder (P = 0.0039);
MVP		0.88
MPC		0.048
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.95
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr16-1306678;