12-112488444-G-T

Position:

• chr12-112488444-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.1381G>T​(p.Ala461Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A461T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense, splice_region
• Scores: Splicing: ADA: 0.9745
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.48

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain Tyrosine-protein phosphatase (size 270) in uniprot entity PTN11_HUMAN there are 52 pathogenic changes around while only 2 benign (96%) in NM_002834.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112488444-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTPN11. . Gene score misZ 3.1293 (greater than the threshold 3.09). Trascript score misZ 4.9438 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome and Noonan-related syndrome, Noonan syndrome with multiple lentigines, metachondromatosis, Noonan syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome 1, Costello syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 12-112488444-G-T is Pathogenic according to our data. Variant chr12-112488444-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 40546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112488444-G-T is described in Lovd as [Pathogenic]. Variant chr12-112488444-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1381G>T	p.Ala461Ser	missense_variant, splice_region_variant	12/16	ENST00000351677.7	NP_002825.3
PTPN11	NM_001330437.2	c.1393G>T	p.Ala465Ser	missense_variant, splice_region_variant	12/16		NP_001317366.1
PTPN11	NM_001374625.1	c.1378G>T	p.Ala460Ser	missense_variant, splice_region_variant	12/16		NP_001361554.1
PTPN11	XM_011538613.3	c.1390G>T	p.Ala464Ser	missense_variant, splice_region_variant	12/16		XP_011536915.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1381G>T	p.Ala461Ser	missense_variant, splice_region_variant	12/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.1393G>T	p.Ala465Ser	missense_variant, splice_region_variant	12/15	5		ENSP00000489597.1
PTPN11	ENST00000635652.1	c.394G>T	p.Ala132Ser	missense_variant, splice_region_variant	4/5	3		ENSP00000489541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2014	The A461S missense mutation in the PTPN11 gene has been reported previously in association with autosomal dominant LEOPARD syndrome (LS) (Osawa, 2009). The Alanine 461 codon lies in a PTP enzyme active site which is a mutational hotspot in PTPN11. A different mutation in the same codon, A461T, has been published in cases of LEOPARD syndrome (Kontaridis, 2005). Therefore, the presence of A461S is consistent with a diagnosis of LEOPARD syndrome. The variant is found in NOONAN panel(s). -

Noonan syndrome with multiple lentigines Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 16, 2009

- -

LEOPARD syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Oct 01, 2021

PM1, PM2, PM5, PP2, PP3, PP5 -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 30, 2023

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala461 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15389709, 15470362, 16377799, 20493809, 23799168, 24718990, 24935154). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 40546). This missense change has been observed in individual(s) with PTPN11-related rasopathies and clinical features of NF1-Noonan syndrome (PMID: 19659470, 22465605, 24790373; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 461 of the PTPN11 protein (p.Ala461Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Uncertain	0.84
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.4	.;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.016	D;.;.
Sift4G	Uncertain	0.040	D;D;T
Polyphen		0.98	D;.;.
Vest4		0.87
MutPred		0.96		Gain of glycosylation at A461 (P = 0.0122);.;.;
MVP		0.96
MPC		1.7
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.83
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: rs121918468; hg19: chr12-112926248; COSMIC: COSV100692090; COSMIC: COSV100692090;