12-112488465-A-G

Position:

• chr12-112488465-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_002834.5(PTPN11):​c.1402A>G​(p.Thr468Ala) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T468M) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 chr12-112488466-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13331.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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, 0.969
• PP5: Variant 12-112488465-A-G is Pathogenic according to our data. Variant chr12-112488465-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 993459.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTPN11	NM_002834.5	c.1402A>G	p.Thr468Ala	missense_variant	12/16	ENST00000351677.7
PTPN11	NM_001330437.2	c.1414A>G	p.Thr472Ala	missense_variant	12/16
PTPN11	NM_001374625.1	c.1399A>G	p.Thr467Ala	missense_variant	12/16
PTPN11	XM_011538613.3	c.1411A>G	p.Thr471Ala	missense_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTPN11	ENST00000351677.7	c.1402A>G	p.Thr468Ala	missense_variant	12/16	1	NM_002834.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1460830 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726786

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2020	The PTPN11 c.1402A>G; p.Thr468Ala variant (rs886039711), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 468 is highly conserved, it occurs in the protein tyrosine phosphatase domain in the catalytic site consensus sequence (Digilio 2002), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (p.Thr468Met, p.Thr468Pro) have been reported in individuals with LEOPARD syndrome, also called Noonan syndrome with multiple lentigines, and are considered disease-causing (Digilio 2002, Martinelli 2008, Motegi 2015). Functional studies of the p.Thr468Ala variant indicate it has slightly decreased catalytic activity and increased affinity for phosphotyrosine peptides, although other substitutions at the same position exhibit more significantly decreased catalytic activity (Martinelli 2008). However, given the lack of clinical data, the significance of the p.Thr468Ala variant is uncertain at this time. References: Digilio MC et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002 Aug;71(2):389-94. Martinelli S et al. Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes. Hum Mol Genet. 2008 Jul 1;17(13):2018-29. Motegi S et al. Pathogenesis of multiple lentigines in LEOPARD syndrome with PTPN11 gene mutation. Acta Derm Venereol. 2015 Nov;95(8):978-84. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
CardioboostCm	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.5	D;.;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.020	D;.;.
Sift4G	Benign	0.065	T;T;T
Polyphen		0.94	P;.;.
Vest4		0.91
MutPred		0.84		Loss of helix (P = 0.1299);.;.;
MVP		0.97
MPC		1.8
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs397507537; hg19: chr12-112926269;