20-50581336-C-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. 16/23 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 the same amino acid substitution has been previously reported as Likely benign in 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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN1	NM_002827.4	c.1160C>T	p.Pro387Leu	missense_variant	Exon 9 of 10	ENST00000371621.5	NP_002818.1
PTPN1	NM_001278618.2	c.941C>T	p.Pro314Leu	missense_variant	Exon 8 of 9		NP_001265547.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN1	ENST00000371621.5	c.1160C>T	p.Pro387Leu	missense_variant	Exon 9 of 10	1	NM_002827.4	ENSP00000360683.3
PTPN1	ENST00000541713.5	c.941C>T	p.Pro314Leu	missense_variant	Exon 8 of 9	2		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

Gnomad4 AFR exome AF: 0.000657 AC: 22 AN: 33480

Gnomad4 AMR exome AF: 0.00315 AC: 141 AN: 44716

Gnomad4 ASJ exome AF: 0.00364 AC: 95 AN: 26132

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00116 AC: 100 AN: 86254

Gnomad4 FIN exome AF: 0.00451 AC: 241 AN: 53412

Gnomad4 NFE exome AF: 0.00697 AC: 7750 AN: 1111870

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.00128 AC: 0.00127545 AN: 0.00127545

Gnomad4 AMR AF: 0.00484 AC: 0.00483534 AN: 0.00483534

Gnomad4 ASJ AF: 0.00547 AC: 0.00547235 AN: 0.00547235

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000621 AC: 0.000621118 AN: 0.000621118

Gnomad4 FIN AF: 0.00471 AC: 0.00470721 AN: 0.00470721

Gnomad4 NFE AF: 0.00734 AC: 0.00733629 AN: 0.00733629

Gnomad4 OTH AF: 0.00756 AC: 0.00756144 AN: 0.00756144

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 v4.3

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
MutationAssessor	Benign	1.4	.;L
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
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

Publications

LitVar

Other links and lift over

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