20-50574654-A-G

Position:

• chr20-50574654-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002827.4(PTPN1):​c.492A>G​(p.Thr164=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00504 in 1,604,760 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (122 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (126 hom.)
• Consequence: PTPN1 NM_002827.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003823
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.32

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-50574654-A-G is Benign according to our data. Variant chr20-50574654-A-G is described in ClinVar as [Benign]. Clinvar id is 773088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN1	NM_002827.4	c.492A>G	p.Thr164=	splice_region_variant, synonymous_variant	5/10	ENST00000371621.5
PTPN1	NM_001278618.2	c.273A>G	p.Thr91=	splice_region_variant, synonymous_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN1	ENST00000371621.5	c.492A>G	p.Thr164=	splice_region_variant, synonymous_variant	5/10	1	NM_002827.4	P1
	ENST00000431019.1	n.908T>C		non_coding_transcript_exon_variant	2/2	2
PTPN1	ENST00000541713.5	c.273A>G	p.Thr91=	splice_region_variant, synonymous_variant	4/9	2

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3572 AN: 152232 Hom.: 122 Cov.: 33

Gnomad AFR AF: 0.0781

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00774 AC: 1846 AN: 238546 Hom.: 53 AF XY: 0.00589 AC XY: 762 AN XY: 129404

Gnomad AFR exome AF: 0.0786

Gnomad AMR exome AF: 0.00644

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000893

Gnomad OTH exome AF: 0.00655

GnomAD4 exome AF: 0.00310 AC: 4509 AN: 1452410 Hom.: 126 Cov.: 30 AF XY: 0.00278 AC XY: 2008 AN XY: 722426

Gnomad4 AFR exome AF: 0.0763

Gnomad4 AMR exome AF: 0.00685

Gnomad4 ASJ exome AF: 0.0240

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000510

Gnomad4 OTH exome AF: 0.00820

GnomAD4 genome AF: 0.0234 AC: 3571 AN: 152350 Hom.: 122 Cov.: 33 AF XY: 0.0229 AC XY: 1709 AN XY: 74502

Gnomad4 AFR AF: 0.0778

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00596 Hom.: 52

Bravo AF: 0.0270

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 21, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

PTPN1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.16
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.028
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: rs35414863; hg19: chr20-49191191;