Genetic Variant NM_012217.3:c.107C>G (chr16-1256540-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012217.3(TPSD1):c.107C>G(p.Thr36Arg) 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 1,458,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T36M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 36)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TPSD1
NM_012217.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

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=0.095332265).

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>G	p.Thr36Arg	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>G	p.Thr36Arg	missense	Exon 2 of 5	ENSP00000211076.3	Q9BZJ3-1
TPSD1	ENST00000397534.6	TSL:5	c.86C>G	p.Thr29Arg	missense	Exon 3 of 6	ENSP00000380668.2	A0A0C4DFZ7
TPSD1	ENST00000711393.1		c.107C>G	p.Thr36Arg	missense	Exon 2 of 5	ENSP00000518724.1	Q9BZJ3-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458110

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725392

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33340

American (AMR)

AF:

0.00

AC:

AN:

44424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25948

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4904

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111138

Other (OTH)

AF:

0.00

AC:

AN:

60180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

0.069

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.040

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.079

M_CAP

Benign

0.054

MetaRNN

Benign

0.095

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

-2.3

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.9

REVEL

Benign

0.22

Sift

Uncertain

0.0070

Sift4G

Benign

0.12

Polyphen

0.19

Vest4

0.10

MutPred

0.31

Gain of MoRF binding (P = 0.0451)

MVP

0.48

MPC

0.011

ClinPred

0.081

GERP RS

-2.4

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.14

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over