Genetic Variant TPST2:p.Arg63Leu (chr22-26541443-C-A) – 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_003595.5(TPST2):c.188G>T(p.Arg63Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R63C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TPST2
NM_003595.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.935

Publications

0 publications found

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]

TPST2 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=0.19053483).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003595.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPST2	NM_003595.5	MANE Select	c.188G>T	p.Arg63Leu	missense	Exon 3 of 7	NP_003586.3
TPST2	NM_001362923.2		c.350G>T	p.Arg117Leu	missense	Exon 4 of 8	NP_001349852.1
TPST2	NM_001008566.3		c.188G>T	p.Arg63Leu	missense	Exon 3 of 7	NP_001008566.1	O60704

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TPST2	ENST00000338754.9	TSL:1 MANE Select	c.188G>T	p.Arg63Leu	missense	Exon 3 of 7	ENSP00000339813.4	O60704
TPST2	ENST00000910417.1		c.188G>T	p.Arg63Leu	missense	Exon 3 of 7	ENSP00000580476.1
TPST2	ENST00000398110.6	TSL:2	c.188G>T	p.Arg63Leu	missense	Exon 3 of 7	ENSP00000381180.2	O60704

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448914

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719764

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33184

American (AMR)

AF:

0.00

AC:

AN:

42878

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25086

East Asian (EAS)

AF:

0.00

AC:

AN:

39544

South Asian (SAS)

AF:

0.00

AC:

AN:

84152

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105890

Other (OTH)

AF:

0.00

AC:

AN:

59742

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

0.19

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

M_CAP

Benign

0.017

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

0.94

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.1

REVEL

Benign

0.13

Sift

Benign

0.26

Sift4G

Benign

0.16

Polyphen

0.20

Vest4

0.36

MutPred

0.37

Loss of MoRF binding (P = 0.0344)

MVP

0.043

MPC

0.75

ClinPred

0.42

GERP RS

4.8

Varity_R

0.55

gMVP

0.77

Mutation Taster

=39/61

disease causing

(source)

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

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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