Genetic Variant NM_012217.3:c.235G>C (chr16-1256668-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_012217.3(TPSD1):c.235G>C(p.Ala79Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 37)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TPSD1
NM_012217.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.28

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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPSD1	NM_012217.3 link	c.235G>C	p.Ala79Pro	missense_variant	Exon 2 of 5	ENST00000211076.5	NP_036349.1	Q9BZJ3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPSD1	ENST00000211076.5 link	c.235G>C	p.Ala79Pro	missense_variant	Exon 2 of 5	1	NM_012217.3	ENSP00000211076.3		Q9BZJ3-1
TPSD1	ENST00000397534.6 link	c.214G>C	p.Ala72Pro	missense_variant	Exon 3 of 6	5		ENSP00000380668.2		A0A0C4DFZ7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152224

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459578

Hom.:

Cov.:

130

AF XY:

0.00

AC XY:

AN XY:

726052

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

.;D

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

.;M

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.66

MutPred

0.91

.;Gain of phosphorylation at T78 (P = 0.3111);

MVP

0.89

MPC

0.060

ClinPred

0.99

GERP RS

3.0

Varity_R

0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over