chr12-112446385-A-G

Variant names:

• chr12-112446385-A-G
• rs397507501
• NM_002834.5:c.124A>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002834.5(PTPN11):​c.124A>G​(p.Thr42Ala) 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: "SCV000057355: Published functional studies demonstrate a significant increase in phosphopeptide binding affinity without greatly altering binding specificity or secondary structure of the domain (Keilhack et al., 2005" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T42S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: 7.31
• Publications: 41 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

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000057355: Published functional studies demonstrate a significant increase in phosphopeptide binding affinity without greatly altering binding specificity or secondary structure of the domain (Keilhack et al., 2005; Muller et al., 2013); SCV000287692: Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 18372317, 23584145).; SCV001361724: This variant exhibits increased affinity for mono-Tyr(P) peptide and phosphopeptide (Keilhack_2005 and Martinelli_2008), which is believed to be one of the mechanisms of SHP2's functional dysregulation. Keilhack_2005, Martinelli_2008; SCV003841251: Functional studies showed increased phosphopeptide binding affinity and dephosphorylation (Martinelli S et al.,2008.); SCV005044098: Functional studies suggest that the p.Thr42Ala variant promotes increased phosphopeptide-binding affinity [PMID:18372317].; SCV005374839: Functional studies showed that this variant results in increased phosphopeptide binding affinity and dephosphorylation supporting the proposed molecular mechanism of its pathogenicity (Martinelli S, et al., 2008).; SCV002669239: "In an assay testing PTPN11 function, this variant showed a functionally abnormal result" (Martinelli S et al. Hum. Mol. Genet., 2008 Jul;17:2018-29).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112446385-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3573673.Status of the report is criteria_provided_single_submitter, 1 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, 0.893
• PP5: Variant 12-112446385-A-G is Pathogenic according to our data. Variant chr12-112446385-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 40482.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.124A>G	p.Thr42Ala	missense	Exon 2 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.124A>G	p.Thr42Ala	missense	Exon 2 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.124A>G	p.Thr42Ala	missense	Exon 2 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.124A>G	p.Thr42Ala	missense	Exon 2 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.124A>G	p.Thr42Ala	missense	Exon 2 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000392597.5	TSL:1	c.124A>G	p.Thr42Ala	missense	Exon 2 of 11	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Noonan syndrome 1 (7)
3	-	-	Noonan syndrome (3)
3	-	-	not provided (3)
2	-	-	RASopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	PTPN11-related disorder (1)
-	-	-	Diffuse midline glioma, H3 K27M-mutant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
CardioboostCm	Uncertain	0.10
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.038	D
MutationAssessor	Benign	0.72	N
PhyloP100		7.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.79
Sift	Benign	0.10	T
Sift4G	Benign	0.077	T
Polyphen		0.60	P
Vest4		0.82
MutPred		0.84		Loss of loop (P = 0.0804)
MVP		0.95
MPC		1.2
ClinPred		0.97	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.81
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397507501; hg19: chr12-112884189; COSMIC: COSV61008667;