20-50579896-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_002827.4(PTPN1):c.1058C>G(p.Pro353Arg) 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: PTPN1 NM_002827.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.157

Genes affected

PTPN1 (HGNC:9642): (protein tyrosine phosphatase non-receptor type 1) The protein encoded by this gene is the founding member of the protein tyrosine phosphatase (PTP) family, which was isolated and identified based on its enzymatic activity and amino acid sequence. PTPs catalyze the hydrolysis of the phosphate monoesters specifically on tyrosine residues. Members of the PTP family share a highly conserved catalytic motif, which is essential for the catalytic activity. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP has been shown to act as a negative regulator of insulin signaling by dephosphorylating the phosphotryosine residues of insulin receptor kinase. This PTP was also reported to dephosphorylate epidermal growth factor receptor kinase, as well as JAK2 and TYK2 kinases, which implicated the role of this PTP in cell growth control, and cell response to interferon stimulation. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PTPN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.06269321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN1	NM_002827.4	c.1058C>G	p.Pro353Arg	missense_variant	8/10	ENST00000371621.5
PTPN1	NM_001278618.2	c.839C>G	p.Pro280Arg	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN1	ENST00000371621.5	c.1058C>G	p.Pro353Arg	missense_variant	8/10	1	NM_002827.4	P1
PTPN1	ENST00000541713.5	c.839C>G	p.Pro280Arg	missense_variant	7/9	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.1058C>G (p.P353R) alteration is located in exon 8 (coding exon 8) of the PTPN1 gene. This alteration results from a C to G substitution at nucleotide position 1058, causing the proline (P) at amino acid position 353 to be replaced by an arginine (R). 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	0.071
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	8.9
Dann	Benign	0.77
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.38	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.063	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.18	N;N
REVEL	Benign	0.019
Sift	Benign	0.23	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.11	.;B
Vest4		0.058
MutPred		0.24		.;Loss of glycosylation at P353 (P = 0.0613);
MVP		0.32
MPC		0.79
ClinPred		0.039	T
GERP RS		0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.16

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: rs2082857071; hg19: chr20-49196433;