chr16-1256540-C-T

Variant names:

• chr16-1256540-C-T
• rs61753433
• NM_012217.3:c.107C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_012217.3(TPSD1):​c.107C>T​(p.Thr36Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,603,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 36)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: TPSD1 NM_012217.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.27

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029282987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSD1	NM_012217.3	c.107C>T	p.Thr36Met	missense_variant	Exon 2 of 5	ENST00000211076.5	NP_036349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPSD1	ENST00000211076.5	c.107C>T	p.Thr36Met	missense_variant	Exon 2 of 5	1	NM_012217.3	ENSP00000211076.3
TPSD1	ENST00000397534.6	c.86C>T	p.Thr29Met	missense_variant	Exon 3 of 6	5		ENSP00000380668.2

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 186 AN: 145840 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.00448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000779

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000954

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000450

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 43 AN: 245536 Hom.: 0 AF XY: 0.000135 AC XY: 18 AN XY: 133390

Gnomad AFR exome AF: 0.00127

Gnomad AMR exome AF: 0.000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000383

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.0000933

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000700 AC: 102 AN: 1458020 Hom.: 0 Cov.: 98 AF XY: 0.0000565 AC XY: 41 AN XY: 725362

Gnomad4 AFR exome AF: 0.00156

Gnomad4 AMR exome AF: 0.000338

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome AF: 0.00130 AC: 190 AN: 145926 Hom.: 0 Cov.: 36 AF XY: 0.00125 AC XY: 89 AN XY: 71336

Gnomad4 AFR AF: 0.00457

Gnomad4 AMR AF: 0.000555

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000781

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000954

Gnomad4 NFE AF: 0.0000450

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000325 Hom.: 0

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.107C>T (p.T36M) alteration is located in exon 2 (coding exon 2) of the TPSD1 gene. This alteration results from a C to T substitution at nucleotide position 107, causing the threonine (T) at amino acid position 36 to be replaced by a methionine (M). 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	Benign	0.16
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	0.77
DANN	Benign	0.92
DEOGEN2	Benign	0.025	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0069	N
LIST_S2	Benign	0.031	T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.0	.;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.36	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.065	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.90	.;P
Vest4		0.10
MVP		0.63
MPC		0.0097
ClinPred		0.0068	T
GERP RS		-2.4
Varity_R		0.022
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61753433; hg19: chr16-1306541;