9-109381726-T-C

Variant names:

• chr9-109381726-T-C
• rs765458684
• NM_002829.4:c.2590A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002829.4(PTPN3):​c.2590A>G​(p.Arg864Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTPN3 NM_002829.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28677928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN3	NM_002829.4	c.2590A>G	p.Arg864Gly	missense_variant	Exon 25 of 26	ENST00000374541.4	NP_002820.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN3	ENST00000374541.4	c.2590A>G	p.Arg864Gly	missense_variant	Exon 25 of 26	5	NM_002829.4	ENSP00000363667.1
PTPN3	ENST00000412145.5	c.2197A>G	p.Arg733Gly	missense_variant	Exon 20 of 21	1		ENSP00000416654.1
PTPN3	ENST00000446349.5	c.2062A>G	p.Arg688Gly	missense_variant	Exon 19 of 20	1		ENSP00000395384.1
PTPN3	ENST00000262539	c.*186A>G		3_prime_UTR_variant	Exon 25 of 26	5		ENSP00000262539.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251492 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

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 Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2590A>G (p.R864G) alteration is located in exon 25 (coding exon 24) of the PTPN3 gene. This alteration results from a A to G substitution at nucleotide position 2590, causing the arginine (R) at amino acid position 864 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	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;.;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.64	.;.;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.070	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.39
MutPred		0.52		.;.;Loss of stability (P = 0.0366);
MVP		0.80
MPC		0.29
ClinPred		0.10	T
GERP RS		4.5
Varity_R		0.72
gMVP		0.42

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

Other links and lift over

dbSNP: rs765458684; hg19: chr9-112144006;