12-112472969-T-A

Position:

chr12-112472969-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS4PP2PM1

This summary comes from the ClinGen Evidence Repository: The c.782T>A (p.Leu261His) variant in PTPN11 is present in 1/6064 “other” alleles in gnomAD v2.1.1; however, it is absent from gnomAD v3 (PM2 not met). It has been identified in 7 independent occurrences in patients with clinical features of a RASopathy (PS4; PMIDs: 28074573, 22253195, 23756559). A functional assay performed on this variant does not meet approved RASopathy VCEP guidelines for criteria application (PS3 not met; PMID:28074573). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot of PTPN11 (PM1; PMID 29493581). PTPN11 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID:29493581). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM1, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6798648/MONDO:0021060/004

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PTPN11
NM_002834.5 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:2

Conservation

PhyloP100: 3.97

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS4

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

PM1

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

PP2

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.782T>A	p.Leu261His	missense_variant	7/16	ENST00000351677.7	NP_002825.3	Q06124-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7 linkuse as main transcript	c.782T>A	p.Leu261His	missense_variant	7/16	1	NM_002834.5	ENSP00000340944.3		Q06124-2
PTPN11	ENST00000635625.1 linkuse as main transcript	c.782T>A	p.Leu261His	missense_variant	7/15	5		ENSP00000489597.1		Q06124-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247456

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134300

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.85e-7

AC:

AN:

1460660

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726724

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RASopathy

Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Mar 16, 2020	The c.782T>A (p.Leu261His) variant in PTPN11 is present in 1/6064 â€œotherâ€ alleles in gnomAD v2.1.1; however, it is absent from gnomAD v3 (PM2 not met). It has been identified in 7 independent occurrences in patients with clinical features of a RASopathy (PS4; PMIDs: 28074573, 22253195, 23756559). A functional assay performed on this variant does not meet approved RASopathy VCEP guidelines for criteria application (PS3 not met; PMID: 28074573). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot of PTPN11 (PM1; PMID 29493581). PTPN11 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM1, PP2. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 13, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu261 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28074573). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 28074573). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 575203). This missense change has been observed in individuals with Noonan syndrome(NS) (PMID: 22253195, 23756559, 28074573). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs765642157, gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 261 of the PTPN11 protein (p.Leu261His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

CardioboostCm

Uncertain

0.67

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.27

.;.;T

Eigen

Benign

-0.088

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Uncertain

0.62

D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

-0.15

N;N;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

2.1

N;N;.

REVEL

Uncertain

0.56

Sift

Benign

0.60

T;T;.

Sift4G

Benign

0.56

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.74

MutPred

0.33

Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);

MVP

0.99

MPC

2.0

ClinPred

0.47

GERP RS

5.7

Varity_R

0.91

gMVP

0.56

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