22-26541329-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_003595.5(TPST2):​c.302G>T​(p.Arg101Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,547,572 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: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

TPST2
NM_003595.5 missense

Scores

11
5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.28
Variant links:
Genes affected
TPST2 (HGNC:12021): (tyrosylprotein sulfotransferase 2) The protein encoded by this gene catalyzes the O-sulfation of tyrosine residues within acidic regions of proteins. The encoded protein is a type II integral membrane protein found in the Golgi body. Alternative splicing produces multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2018]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a mutagenesis_site Prevents dimerization and strongly decreases enzyme activity. (size 0) in uniprot entity TPST2_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TPST2NM_003595.5 linkuse as main transcriptc.302G>T p.Arg101Leu missense_variant 3/7 ENST00000338754.9 NP_003586.3 O60704A0A024R1G9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TPST2ENST00000338754.9 linkuse as main transcriptc.302G>T p.Arg101Leu missense_variant 3/71 NM_003595.5 ENSP00000339813.4 O60704

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152236
Hom.:
0
Cov.:
33
show subpopulations
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000203
AC:
4
AN:
197346
Hom.:
0
AF XY:
0.00000951
AC XY:
1
AN XY:
105190
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:
0.0000444
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000373
AC:
52
AN:
1395336
Hom.:
0
Cov.:
73
AF XY:
0.0000306
AC XY:
21
AN XY:
685940
show subpopulations
Gnomad4 AFR exome
AF:
0.0000313
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000264
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000436
Gnomad4 OTH exome
AF:
0.0000174
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152236
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000251
AC:
3

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 submitterclinical testingAmbry GeneticsOct 25, 2024The c.302G>T (p.R101L) alteration is located in exon 3 (coding exon 1) of the TPST2 gene. This alteration results from a G to T substitution at nucleotide position 302, causing the arginine (R) at amino acid position 101 to be replaced by a leucine (L). 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
1.0
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.67
D;D;D;.;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
.;.;D;D;D
M_CAP
Benign
0.058
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D
MetaSVM
Benign
-0.31
T
MutationAssessor
Pathogenic
3.0
M;M;M;.;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-7.0
D;D;D;D;D
REVEL
Uncertain
0.48
Sift
Uncertain
0.0020
D;D;D;D;D
Sift4G
Uncertain
0.018
D;D;D;.;D
Polyphen
1.0
D;D;D;.;.
Vest4
0.92
MutPred
0.59
Loss of MoRF binding (P = 0.0181);Loss of MoRF binding (P = 0.0181);Loss of MoRF binding (P = 0.0181);Loss of MoRF binding (P = 0.0181);Loss of MoRF binding (P = 0.0181);
MVP
0.58
MPC
1.7
ClinPred
0.94
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.90
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs761692971; hg19: chr22-26937295; API