NM_002834.5:c.182A>G

Variant names:

• chr12-112450362-A-G
• rs121918461
• NM_002834.5:c.182A>G

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.182A>G​(p.Asp61Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,050 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: "SCV004014682: Functional assays have demonstrated that the variant enhances basal protein activity (gain of function) (PMID:15987685).; SCV000549993: Experimental studies have shown that this missense change affects PTPN11 function (PMID:15273746, 15987685, 16377799, 19008228).; SCV001338338: Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a gain of function leading to activation of the Ras-ErK signaling pathway (example, Hu_2015).; SCV000057369: Published functional studies demonstrate that p.(D61G) leads to enhanced basal activity of the protein compared to wild type (gain of function effect) (Keilhack et al., 2005); SCV000206706: "In vitro functional analyses demonstrate that this variant causes increased basal activity of the PTPN11 protein and mouse and zebrafish models expressing this variant have features that are consistent with Noonan syndrome". PMID:15273746 PMID:24718990 PMID:15987685 PMID:16377799 PMID:11992261 PMID:20651068; SCV001746164: PS3:Supporting; SCV000199995: Both in vivo animal models and in vitro studies provide evidence that this variant impacts protein function (Araki 2004, Kontaridis 2006, Uhlen 2006, Eminaga 2008, Wang 2009, Xu 2010, De Rocca 2012, Bonetti 2014, Lee 2014).; SCV004721419: "In vitro functional studies and knock-in mouse models are consistent with this variant disrupting normal protein function (Araki et al. 2004. PubMed ID: 15273746; Keilhack et al. 2005. PubMed ID: 15987685; Serra-Nédélec. 2012. PubMed ID: 22371576)."". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D61Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:29
• Conservation: PhyloP100: 9.31
• Publications: 221 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 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004014682: Functional assays have demonstrated that the variant enhances basal protein activity (gain of function) (PMID: 15987685).; SCV000549993: Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15273746, 15987685, 16377799, 19008228).; SCV001338338: Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a gain of function leading to activation of the Ras-ErK signaling pathway (example, Hu_2015).; SCV000057369: Published functional studies demonstrate that p.(D61G) leads to enhanced basal activity of the protein compared to wild type (gain of function effect) (Keilhack et al., 2005); SCV000206706: "In vitro functional analyses demonstrate that this variant causes increased basal activity of the PTPN11 protein and mouse and zebrafish models expressing this variant have features that are consistent with Noonan syndrome". PMID:15273746 PMID:24718990 PMID:15987685 PMID:16377799 PMID:11992261 PMID:20651068; SCV001746164: PS3:Supporting; SCV000199995: Both in vivo animal models and in vitro studies provide evidence that this variant impacts protein function (Araki 2004, Kontaridis 2006, Uhlen 2006, Eminaga 2008, Wang 2009, Xu 2010, De Rocca 2012, Bonetti 2014, Lee 2014).; SCV004721419: "In vitro functional studies and knock-in mouse models are consistent with this variant disrupting normal protein function (Araki et al. 2004. PubMed ID: 15273746; Keilhack et al. 2005. PubMed ID: 15987685; Serra-Nédélec. 2012. PubMed ID: 22371576)."
• PM1: In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr12-112450361-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228392.
• 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, 0.966
• PP5: Variant 12-112450362-A-G is Pathogenic according to our data. Variant chr12-112450362-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13330.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.182A>G	p.Asp61Gly	missense	Exon 3 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.182A>G	p.Asp61Gly	missense	Exon 3 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.179A>G	p.Asp60Gly	missense	Exon 3 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.182A>G	p.Asp61Gly	missense	Exon 3 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.182A>G	p.Asp61Gly	missense	Exon 3 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000392597.5	TSL:1	c.182A>G	p.Asp61Gly	missense	Exon 3 of 11	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461050 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726854

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111300

Other (OTH) AF: 0.0000166 AC: 1 AN: 60356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

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
9	-	-	not provided (9)
8	-	-	Noonan syndrome 1 (8)
3	-	-	RASopathy (3)
2	-	-	LEOPARD syndrome 1 (2)
1	-	-	Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)
1	-	-	Metachondromatosis (1)
1	-	-	Non-immune hydrops fetalis (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia (1)
1	-	-	PTPN11-related disorder (1)
1	-	-	Short stature;C4049796:Abnormal cardiovascular system morphology (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	0.59	N
PhyloP100		9.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.057	T
Polyphen		0.82	P
Vest4		0.98
MutPred		0.91		Loss of solvent accessibility (P = 0.0674)
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.75
Mutation Taster		=0/100	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: rs121918461; hg19: chr12-112888166; COSMIC: COSV61005256; COSMIC: COSV61005256;