12-112453279-G-T

Variant names:

• chr12-112453279-G-T
• rs397507520
• NM_002834.5:c.417G>T

Variant summary

Our verdict is Pathogenic. The variant received 25 ACMG points: 25P and 0B. PS1_Very_Strong PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.417G>T​(p.Glu139Asp) variant causes a missense change. 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E139G) 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:8
• Conservation: PhyloP100: 3.63
• Publications: 63 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

ENSG00000305447 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 25 ACMG points.

• PS1: Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112453278-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2095543.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 Costello syndrome, Noonan syndrome 1, Noonan syndrome, LEOPARD syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, metachondromatosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 12-112453279-G-T is Pathogenic according to our data. Variant chr12-112453279-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 40512.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.417G>T	p.Glu139Asp	missense	Exon 4 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.417G>T	p.Glu139Asp	missense	Exon 4 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.414G>T	p.Glu138Asp	missense	Exon 4 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.417G>T	p.Glu139Asp	missense	Exon 4 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.417G>T	p.Glu139Asp	missense	Exon 4 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000392597.5	TSL:1	c.417G>T	p.Glu139Asp	missense	Exon 4 of 11	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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
3	-	-	not provided (3)
2	-	-	Noonan syndrome 1 (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.1	L
PhyloP100		3.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.78
MutPred		0.90		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.98
MPC		1.8
ClinPred		0.96	D
GERP RS		4.5
PromoterAI		0.0094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.71
gMVP		0.61
Mutation Taster		=2/98	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: rs397507520; hg19: chr12-112891083; COSMIC: COSV61007093; COSMIC: COSV61007093;