rs16995309

chr20-50581336-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_002827.4(PTPN1):c.1160C>T(p.Pro387Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00583 in 1,614,032 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0049 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (23 hom.)
• Consequence: PTPN1 NM_002827.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66

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 Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PTPN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0034552217).
• BS2: High AC in GnomAd at 743 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN1	NM_002827.4	c.1160C>T	p.Pro387Leu	missense_variant	9/10	ENST00000371621.5
PTPN1	NM_001278618.2	c.941C>T	p.Pro314Leu	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN1	ENST00000371621.5	c.1160C>T	p.Pro387Leu	missense_variant	9/10	1	NM_002827.4	P1
PTPN1	ENST00000541713.5	c.941C>T	p.Pro314Leu	missense_variant	8/9	2

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 743 AN: 152192 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00734

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00475 AC: 1194 AN: 251178 Hom.: 6 AF XY: 0.00493 AC XY: 670 AN XY: 135782

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.00762

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00593 AC: 8668 AN: 1461722 Hom.: 23 Cov.: 31 AF XY: 0.00580 AC XY: 4215 AN XY: 727134

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00364

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.00451

Gnomad4 NFE exome AF: 0.00697

Gnomad4 OTH exome AF: 0.00498

GnomAD4 genome AF: 0.00488 AC: 743 AN: 152310 Hom.: 3 Cov.: 32 AF XY: 0.00448 AC XY: 334 AN XY: 74472

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.00734

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00652 Hom.: 2

Bravo AF: 0.00467

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00526 AC: 639

EpiCase AF: 0.00742

EpiControl AF: 0.00895

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	7.6
Dann	Benign	0.70
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.022
Sift	Benign	0.078	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.072	.;B
Vest4		0.047
MVP		0.082
MPC		0.76
ClinPred		0.0044	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.37

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: rs16995309; hg19: chr20-49197873; COSMIC: COSV50386130; COSMIC: COSV50386130;