Genetic Variant TPST1:p.Lys301Glu (chr7-66286566-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_003596.4(TPST1):c.901A>G(p.Lys301Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,609,784 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TPST1
NM_003596.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.19

Variant links:

Genes affected

TPST1 (HGNC:12020): (tyrosylprotein sulfotransferase 1) Enables protein homodimerization activity and protein-tyrosine sulfotransferase activity. Involved in peptidyl-tyrosine sulfation. Is integral component of Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

TPST1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity TPST1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPST1	NM_003596.4 link	c.901A>G	p.Lys301Glu	missense_variant	Exon 3 of 6	ENST00000304842.6	NP_003587.1	O60507A0A024RDK9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TPST1	ENST00000304842.6 link	c.901A>G	p.Lys301Glu	missense_variant	Exon 3 of 6	1	NM_003596.4	ENSP00000302413.5	O60507
TPST1	ENST00000480281.5 link	n.245A>G		non_coding_transcript_exon_variant	Exon 2 of 5	1
TPST1	ENST00000649664.1 link	c.901A>G	p.Lys301Glu	missense_variant	Exon 4 of 7			ENSP00000497281.1	O60507

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

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:

0.00000804

AC:

AN:

248678

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134494

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000587

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:

0.00000274

AC:

AN:

1457584

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000676

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

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

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.901A>G (p.K301E) alteration is located in exon 3 (coding exon 2) of the TPST1 gene. This alteration results from a A to G substitution at nucleotide position 901, causing the lysine (K) at amino acid position 301 to be replaced by a glutamic acid (E). 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

0.60

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Benign

0.041

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.9

M;M

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.5

D;.

REVEL

Uncertain

0.53

Sift

Uncertain

0.0060

D;.

Sift4G

Uncertain

0.016

D;.

Polyphen

1.0

D;D

Vest4

0.87

MutPred

0.50

Loss of MoRF binding (P = 0.0069);Loss of MoRF binding (P = 0.0069);

MVP

0.76

MPC

0.97

ClinPred

0.94

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.78

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.

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