NM_002827.4:c.1160C>T

Variant names:

• chr20-50581336-C-T
• rs16995309
• NM_002827.4:c.1160C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 27 publications found

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]

PTPN1 Gene-Disease associations (from GenCC):

• autoinflammatory syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034552217).
• BS2: High AC in GnomAd4 at 743 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002827.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN1	NM_002827.4	MANE Select	c.1160C>T	p.Pro387Leu	missense	Exon 9 of 10	NP_002818.1
	PTPN1	NM_001278618.2		c.941C>T	p.Pro314Leu	missense	Exon 8 of 9	NP_001265547.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN1	ENST00000371621.5	TSL:1 MANE Select	c.1160C>T	p.Pro387Leu	missense	Exon 9 of 10	ENSP00000360683.3
	PTPN1	ENST00000541713.5	TSL:2	c.941C>T	p.Pro314Leu	missense	Exon 8 of 9	ENSP00000437732.1

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

GnomAD2 exomes AF: 0.00475 AC: 1194 AN: 251178 AF XY: 0.00493

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 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

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.00315 AC: 141 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00364 AC: 95 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00116 AC: 100 AN: 86254

European-Finnish (FIN) AF: 0.00451 AC: 241 AN: 53412

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.00697 AC: 7750 AN: 1111870

Other (OTH) AF: 0.00498 AC: 301 AN: 60390

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

African (AFR) AF: 0.00128 AC: 53 AN: 41554

American (AMR) AF: 0.00484 AC: 74 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00734 AC: 499 AN: 68018

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00650 Hom.: 7

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 v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.7
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.022
Sift	Benign	0.078	T
Sift4G	Benign	0.21	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
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

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