chr12-112489083-G-C

Variant names:

• chr12-112489083-G-C
• rs397507545
• NM_002834.5:c.1507G>C

Variant summary

Our verdict is Pathogenic. The variant received 31 ACMG points: 31P and 0B. PS1_Very_Strong PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.1507G>C​(p.Gly503Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002702418: Based on internal structural analysis, this variant is more destabilizing than other nearby pathogenic variants (Hof P et al. Cell, 1998 Feb" and additional evidence is available in ClinVar. 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. G503A) has been classified as 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:20
• Conservation: PhyloP100: 9.60
• Publications: 66 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

LOC124903024 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 31 ACMG points.

• PS1: Transcript NM_002834.5 (PTPN11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002702418: Based on internal structural analysis, this variant is more destabilizing than other nearby pathogenic variants (Hof P et al. Cell, 1998 Feb;92:441-50).
• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 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 chr12-112489084-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 162464.Status of the report is no_assertion_criteria_provided, 0 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, 0.988
• PP5: Variant 12-112489083-G-C is Pathogenic according to our data. Variant chr12-112489083-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 40558.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.1507G>C	p.Gly503Arg	missense	Exon 13 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.1519G>C	p.Gly507Arg	missense	Exon 13 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.1504G>C	p.Gly502Arg	missense	Exon 13 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.1507G>C	p.Gly503Arg	missense	Exon 13 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.1519G>C	p.Gly507Arg	missense	Exon 13 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000635652.1	TSL:3	c.520G>C	p.Gly174Arg	missense	Exon 5 of 5	ENSP00000489541.1	A0A0U1RRI0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251492 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

⚠️ 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: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Noonan syndrome 1 (6)
6	-	-	not provided (6)
2	-	-	RASopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 (1)
1	-	-	Monogenic short statue (1)
1	-	-	Neurodevelopmental disorder (1)
1	-	-	Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia (1)
1	-	-	PTPN11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.93		Gain of MoRF binding (P = 0.0178)
MVP		0.99
MPC		2.1
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.95
Mutation Taster		=5/95	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: rs397507545; hg19: chr12-112926887; COSMIC: COSV61005824; COSMIC: COSV61005824;