12-112477720-A-G

Variant names:

• chr12-112477720-A-G
• rs121918455
• NM_002834.5:c.923A>G

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.923A>G​(p.Asn308Ser) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002761708: In vitro functional studies have shown that this variant alters substrate specificity and increased catalytic activity relative to the wildtype protein (PMID:15987685) (PS3)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N308D) has been classified as Pathogenic. The gene PTPN11 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:40 O:2
• Conservation: PhyloP100: 8.89
• Publications: 75 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 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002761708: In vitro functional studies have shown that this variant alters substrate specificity and increased catalytic activity relative to the wildtype protein (PMID:15987685) (PS3).; SCV000260037: Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PTPN11 function with a positive predictive value of 95%.; SCV000057423: Published functional studies demonstrate a damaging effect showing that the variant impacts substrate specificity of the catalytic site (Keilhack et al., 2005); PMID: 24803665; SCV000206717: "In vitro functional analyses demonstrate that the Asn308Ser variant has altered substrate specificity and increased catalytic activity relative to the wildtype protein (Keilhack 2005), consistent with established disease mechanisms of Noonan syndrome (Tartaglia 2001)."; SCV000698086: Functional assays suggest that this variant alters substrate specificity (Keilhack_JBC_2005), and N308S SHP-2-expressing fetal liver cells also displayed a hypersensitive pattern of CFU-GM colony growth in response to GM-CSF (Schubbert_Blood_2005).; SCV004175774: Functional studies demonstrate a damaging effect showing that the variant impacts substrate specificity of the catalytic site (Keilhack et al., 2005).; SCV001443765: Functional studies of p.Asn308Ser have shown that it alters substrate specificity at the catalytic site (PMID: 15987685).; SCV004726164: Functional studies of this variant demonstrate increased catalytic activity and altered substrate specificity compared to wild type PTPN11 (Keilhack et al. 2005. PubMed ID: 15987685).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112477719-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13326.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 12-112477720-A-G is Pathogenic according to our data. Variant chr12-112477720-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13327.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.923A>G	p.Asn308Ser	missense	Exon 8 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.923A>G	p.Asn308Ser	missense	Exon 8 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.920A>G	p.Asn307Ser	missense	Exon 8 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.923A>G	p.Asn308Ser	missense	Exon 8 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.923A>G	p.Asn308Ser	missense	Exon 8 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000392597.5	TSL:1	c.923A>G	p.Asn308Ser	missense	Exon 8 of 11	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000462 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Noonan syndrome 1 (14)
10	-	-	not provided (10)
5	-	-	Noonan syndrome (5)
3	-	-	LEOPARD syndrome 1 (3)
2	-	-	PTPN11-related disorder (2)
2	-	-	RASopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)
1	-	-	LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)
1	-	-	Noonan syndrome 3 (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
CardioboostCm	Uncertain	0.18
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.83	L
PhyloP100		8.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.69
Sift	Benign	0.072	T
Sift4G	Benign	0.39	T
Polyphen		0.34	B
Vest4		0.89
MutPred		0.92		Loss of stability (P = 0.0668)
MVP		0.87
MPC		0.65
ClinPred		0.99	D
GERP RS		5.6
PromoterAI		0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.70
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121918455; hg19: chr12-112915524; COSMIC: COSV61006976; COSMIC: COSV61006976;