Genetic Variant PTPN3:p.Cys774Gly (chr9-109383485-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002829.4(PTPN3):c.2320T>G(p.Cys774Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. C774S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

PTPN3
NM_002829.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.25

Publications

3 publications found

Variant links:

Genes affected

PTPN3 (HGNC:9655): (protein tyrosine phosphatase non-receptor type 3) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This protein contains a C-terminal PTP domain and an N-terminal domain homologous to the band 4.1 superfamily of cytoskeletal-associated proteins. P97, a cell cycle regulator involved in a variety of membrane related functions, has been shown to be a substrate of this PTP. This PTP was also found to interact with, and be regulated by adaptor protein 14-3-3 beta. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2009]

PTPN3 Gene-Disease associations (from GenCC):

schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

PTPN3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002829.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN3	NM_002829.4	MANE Select	c.2320T>G	p.Cys774Gly	missense	Exon 23 of 26	NP_002820.3
PTPN3	NM_001145368.2		c.2185T>G	p.Cys729Gly	missense	Exon 22 of 25	NP_001138840.1	B7Z9V1
PTPN3	NM_001145369.2		c.1927T>G	p.Cys643Gly	missense	Exon 18 of 21	NP_001138841.1	P26045-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN3	ENST00000374541.4	TSL:5 MANE Select	c.2320T>G	p.Cys774Gly	missense	Exon 23 of 26	ENSP00000363667.1	P26045-1
PTPN3	ENST00000412145.5	TSL:1	c.1927T>G	p.Cys643Gly	missense	Exon 18 of 21	ENSP00000416654.1	P26045-2
PTPN3	ENST00000446349.5	TSL:1	c.1792T>G	p.Cys598Gly	missense	Exon 17 of 20	ENSP00000395384.1	P26045-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.4

PhyloP100

9.2

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-10

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.018

Polyphen

1.0

Vest4

0.96

MutPred

0.71

Gain of disorder (P = 0.0369)

MVP

0.96

MPC

0.95

ClinPred

1.0

GERP RS

4.8

Varity_R

0.96

gMVP

0.75

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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