rs121918468

Variant names:

• chr12-112488444-G-A
• rs121918468
• NM_002834.5:c.1381G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-112488444-G-A
• chr12-112488444-G-T
• chr12-112488444-G-C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_002834.5(PTPN11):​c.1381G>A​(p.Ala461Thr) 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. 16/25 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000057435: Published functional studies demonstrate this variant results in either a dramatic reduction of catalytic activity or complete catalytic inactivity (Yu et al., 2014" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A461G) has been classified as Likely pathogenic. The gene PTPN11 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense, splice_region
• Scores: Splicing: ADA: 0.9800
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:3
• Conservation: PhyloP100: 9.48
• Publications: 49 publications found

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 Gene-Disease associations (from GenCC):

• LEOPARD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for PTPN11 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000057435: Published functional studies demonstrate this variant results in either a dramatic reduction of catalytic activity or complete catalytic inactivity (Yu et al., 2014; Kontaridis et al., 2006);; SCV000061272: "In-vitro and in-vivo functional studies suggest this variant has a dominant negative effect, which is an established pathogenic mechanism in LEOPARD (Kontaridis 2006, Stewart 2010, Yu 2014)."; SCV000659032: Experimental studies have shown that this missense change affects PTPN11 function (PMID: 16377799, 20493809, 24718990, 24935154).; SCV000698054: Functional studies report the variant effect results in catalytic inactivity and was shown to strongly inhibiting EGF-evoked Erk activation in a dominant-negative manner (Kontaridis_2006, Yu_2014).; SCV001159835: Biochemical characterization of p.Ala461Thr PTPN11 variant protein shows severely reduced phosphatase activity (Kontaridis 2006, Yu 2014). This variant also fails to rescue developmental defects of a zebrafish shp2 (PTPN11) morphant to the same extent as wildtype (Bonetti 2014, Stewart 2010).; SCV004114248: Two studies found the p.Ala461Thr variant imparts a dominant-negative effect resulting in a reduction in RAS pathway signaling (Kontaridis et al. 2006. PubMed ID: 16377799; Stewart et al. 2010. PubMed ID: 20493809). Consistent with the previous studies, another found the variant does result in lower catalytic activity; however, the activation of PTPN11 was prolonged (Yu et al. 2014. PubMed ID: 24935154).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain 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 chr12-112488445-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 55798.
• PP2: Missense variant in the PTPN11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.1293 (above the threshold of 3.09). Trascript score misZ: 4.9438 (above the threshold of 3.09). GenCC associations: The gene is linked to LEOPARD syndrome 1, metachondromatosis, Noonan syndrome with multiple lentigines, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome, Costello syndrome.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 12-112488444-G-A is Pathogenic according to our data. Variant chr12-112488444-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	NM_002834.5	MANE Select	c.1381G>A	p.Ala461Thr	missense splice_region	Exon 12 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.1393G>A	p.Ala465Thr	missense splice_region	Exon 12 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.1378G>A	p.Ala460Thr	missense splice_region	Exon 12 of 16	NP_001361554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.1381G>A	p.Ala461Thr	missense splice_region	Exon 12 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.1393G>A	p.Ala465Thr	missense splice_region	Exon 12 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000635652.1	TSL:3	c.394G>A	p.Ala132Thr	missense splice_region	Exon 4 of 5	ENSP00000489541.1	A0A0U1RRI0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000494 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	LEOPARD syndrome 1 (4)
2	-	-	Noonan syndrome 1 (2)
2	-	-	not provided (2)
2	-	-	RASopathy (2)
1	-	-	Noonan syndrome with multiple lentigines (1)
1	-	-	not specified (1)
1	-	-	PTPN11-related disorder (1)
-	-	-	Diffuse midline glioma, H3 K27M-mutant (1)
-	-	-	Embryonal rhabdomyosarcoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.98		Loss of helix (P = 0.1299)
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.98
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.89
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

Other links and lift over

dbSNP: rs121918468; hg19: chr12-112926248; COSMIC: COSV61005148; COSMIC: COSV61005148;