16-1256669-C-G

Position:

chr16-1256669-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_012217.3(TPSD1):c.236C>G(p.Ala79Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,611,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 37)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TPSD1
NM_012217.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.809

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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPSD1	NM_012217.3 linkuse as main transcript	c.236C>G	p.Ala79Gly	missense_variant	2/5	ENST00000211076.5	NP_036349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPSD1	ENST00000211076.5 linkuse as main transcript	c.236C>G	p.Ala79Gly	missense_variant	2/5	1	NM_012217.3	ENSP00000211076	P2	Q9BZJ3-1
TPSD1	ENST00000397534.6 linkuse as main transcript	c.215C>G	p.Ala72Gly	missense_variant	3/6	5		ENSP00000380668	A2
TPSD1	ENST00000711393.1 linkuse as main transcript	c.236C>G	p.Ala79Gly	missense_variant	2/5			ENSP00000518724	A2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248786

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134620

show subpopulations

Gnomad AFR exome

AF:

0.000186

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1459540

Hom.:

Cov.:

130

AF XY:

0.00000275

AC XY:

AN XY:

725998

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

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:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.0000654

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

Bravo

AF:

0.0000945

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.236C>G (p.A79G) alteration is located in exon 2 (coding exon 2) of the TPSD1 gene. This alteration results from a C to G substitution at nucleotide position 236, causing the alanine (A) at amino acid position 79 to be replaced by a glycine (G). 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

Pathogenic

0.73

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

.;D

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.037

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.5

.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.46

MutPred

0.92

.;Gain of catalytic residue at A80 (P = 0.2246);

MVP

0.87

MPC

0.035

ClinPred

0.99

GERP RS

3.0

Varity_R

0.75

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over