Variant 12-112446309-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.48A>G (p.Ala16=) variant in the PTPN11 gene is 0.0284% (9/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA134668/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

PTPN11
NM_002834.5 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:10

Conservation

PhyloP100: -0.0330

Variant links:

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]

PTPN11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5 linkuse as main transcript	c.48A>G	p.Ala16=	synonymous_variant	2/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 linkuse as main transcript	c.48A>G	p.Ala16=	synonymous_variant	2/16	1	NM_002834.5	ENSP00000340944	A1	Q06124-2

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000278

AC:

AN:

251442

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000882

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000325

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000510

AC:

746

AN:

1461792

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

389

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000916

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000553

Gnomad4 OTH exome

AF:

0.000745

GnomAD4 genome

AF:

0.000296

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000389

Hom.:

Bravo

AF:

0.000249

EpiCase

AF:

0.000654

EpiControl

AF:

0.000474

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 17, 2016	Variant summary: The PTPN11 c.48A>G (p.Ala16Ala) variant causes a synonymous change with 4/5 splice prediction tools predict no significant impact on normal splicing and no alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 34/121402 (1/3570), which exceeds the estimated maximal expected allele frequency for a pathogenic PTPN11 variant of 1/16000, therefore, suggesting this variant is likely a benign polymorphism. In addition, a reputable clinical diagnostic laboratory cites the variant as "likely benign." Therefore, the variant of interest has been classified as Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	PTPN11: BP4, BP7 -

RASopathy

Benign:2

Likely benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 18, 2017	The filtering allele frequency of the c.48A>G (p.Ala16=) variant in the PTPN11 gene is 0.0284% (9/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

Noonan syndrome 1

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 10, 2014

p.Ala16Ala in exon 2 of PTPN11: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 22/66740 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org/; dbSNP rs372736227). -

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. -

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. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2019

This alteration is classified as likely 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. -

Noonan syndrome and Noonan-related syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

8.7

DANN

Benign

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over