rs41304351

chr12-112453399-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002834.5(PTPN11):c.525+12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,374 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.010 (17 hom., cov: 32)
  • Exomes 𝑓: 0.013 (147 hom.)
• Consequence: PTPN11 NM_002834.5 intron
• Clinical Significance: Benign reviewed by expert panel B:17
• Conservation: PhyloP100: -1.29

Genes affected

PTPN11 (HGNC:9644): (protein tyrosine phosphatase non-receptor type 11) The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. 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 contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-112453399-G-C is Benign according to our data. Variant chr12-112453399-G-C is described in ClinVar as [Benign]. Clinvar id is 40516.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-112453399-G-C is described in Lovd as [Benign]. Variant chr12-112453399-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0102 (1560/152322) while in subpopulation AMR AF= 0.0218 (334/15294). AF 95% confidence interval is 0.0199. There are 17 homozygotes in gnomad4. There are 715 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1563 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.525+12G>C		intron_variant		ENST00000351677.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.525+12G>C		intron_variant		1	NM_002834.5	A1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1563 AN: 152204 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0100 AC: 2522 AN: 251322 Hom.: 25 AF XY: 0.0101 AC XY: 1370 AN XY: 135830

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0134 AC: 19579 AN: 1461052 Hom.: 147 Cov.: 31 AF XY: 0.0130 AC XY: 9453 AN XY: 726856

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.00808

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.00281

Gnomad4 NFE exome AF: 0.0158

Gnomad4 OTH exome AF: 0.0131

GnomAD4 genome AF: 0.0102 AC: 1560 AN: 152322 Hom.: 17 Cov.: 32 AF XY: 0.00960 AC XY: 715 AN XY: 74484

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.0218

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.0150

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0113 Hom.: 2

Bravo AF: 0.0117

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 19, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2006	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

RASopathy Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The filtering allele frequency of the c.525+12G>C variant in the PTPN11 gene is 1.4% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (969/66644 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additional case level data available: SCV000057399.8; SCV000061311.5; SCV000248623.2; SCV000206755.1; SCV000207666.1. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Metachondromatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

LEOPARD syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Noonan syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Juvenile myelomonocytic leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Noonan syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 25, 2018

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.22
Dann	Benign	0.48

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: rs41304351; hg19: chr12-112891203; COSMIC: COSV100692736;