16-1256668-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_012217.3(TPSD1):​c.235G>T​(p.Ala79Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,584 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 37)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TPSD1
NM_012217.3 missense

Scores

7
9
3

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.957

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TPSD1NM_012217.3 linkc.235G>T p.Ala79Ser 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
TPSD1ENST00000211076.5 linkc.235G>T p.Ala79Ser missense_variant Exon 2 of 5 1 NM_012217.3 ENSP00000211076.3 Q9BZJ3-1
TPSD1ENST00000397534.6 linkc.214G>T p.Ala72Ser missense_variant Exon 3 of 6 5 ENSP00000380668.2 A0A0C4DFZ7

Frequencies

GnomAD3 genomes
Cov.:
37
GnomAD3 exomes
AF:
0.00000804
AC:
2
AN:
248762
Hom.:
0
AF XY:
0.0000149
AC XY:
2
AN XY:
134648
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000179
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459584
Hom.:
0
Cov.:
130
AF XY:
0.00000138
AC XY:
1
AN XY:
726052
show subpopulations
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
37
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Pathogenic
0.14
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.46
.;T
Eigen
Uncertain
0.22
Eigen_PC
Benign
0.0047
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Benign
1.7
.;L
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-2.8
D;D
REVEL
Pathogenic
0.74
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.50
MutPred
0.92
.;Gain of catalytic residue at A79 (P = 0.3413);
MVP
0.85
MPC
0.062
ClinPred
0.98
D
GERP RS
3.0
Varity_R
0.56
gMVP
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs373075240; hg19: chr16-1306669; API