Genetic Variant NM_012217.3:c.107C>T (chr16-1256540-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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. 14/22 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.27

Publications

0 publications found

Variant links:

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]

TPSD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029282987).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012217.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPSD1	NM_012217.3	MANE Select	c.107C>T	p.Thr36Met	missense	Exon 2 of 5	NP_036349.1	Q9BZJ3-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPSD1	ENST00000211076.5	TSL:1 MANE Select	c.107C>T	p.Thr36Met	missense	Exon 2 of 5	ENSP00000211076.3	Q9BZJ3-1
TPSD1	ENST00000397534.6	TSL:5	c.86C>T	p.Thr29Met	missense	Exon 3 of 6	ENSP00000380668.2	A0A0C4DFZ7
TPSD1	ENST00000711393.1		c.107C>T	p.Thr36Met	missense	Exon 2 of 5	ENSP00000518724.1	Q9BZJ3-2

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

186

AN:

145840

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000175

AC:

AN:

245536

AF XY:

0.000135

show subpopulations

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 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.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

725362

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00156

AC:

AN:

33274

American (AMR)

AF:

0.000338

AC:

AN:

44418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.000126

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86028

European-Finnish (FIN)

AF:

0.0000381

AC:

AN:

52464

Middle Eastern (MID)

AF:

0.000612

AC:

AN:

4902

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1111134

Other (OTH)

AF:

0.000233

AC:

AN:

60172

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.348

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00130

AC:

190

AN:

145926

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

AN XY:

71336

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00457

AC:

174

AN:

38042

American (AMR)

AF:

0.000555

AC:

AN:

14412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3290

East Asian (EAS)

AF:

0.000781

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4712

European-Finnish (FIN)

AF:

0.0000954

AC:

AN:

10482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

66730

Other (OTH)

AF:

0.00

AC:

AN:

2002

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.344

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000325

Hom.:

ExAC

AF:

0.000107

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.77

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.025

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.031

M_CAP

Benign

0.068

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.0

PhyloP100

-2.3

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.36

REVEL

Uncertain

0.29

Sift

Benign

0.065

Sift4G

Benign

0.11

Polyphen

0.90

Vest4

0.10

MVP

0.63

MPC

0.0097

ClinPred

0.0068

GERP RS

-2.4

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.022

gMVP

0.61

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over