12-112419121-C-G

Variant names:

• chr12-112419121-C-G
• rs886041517
• NM_002834.5:c.10C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2 PM5 PP2 PP5 BP4

The NM_002834.5(PTPN11):​c.10C>G​(p.Arg4Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,373,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R4Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.40
• Publications: 2 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112419122-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2729546.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.
• PP5: Variant 12-112419121-C-G is Pathogenic according to our data. Variant chr12-112419121-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 280283.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40868947). . Strength limited to SUPPORTING due to the PP5.

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.10C>G	p.Arg4Gly	missense	Exon 1 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.10C>G	p.Arg4Gly	missense	Exon 1 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.10C>G	p.Arg4Gly	missense	Exon 1 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.10C>G	p.Arg4Gly	missense	Exon 1 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.10C>G	p.Arg4Gly	missense	Exon 1 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000392597.5	TSL:1	c.10C>G	p.Arg4Gly	missense	Exon 1 of 11	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1373876 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 677950

⚠️ 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: 28884

American (AMR) AF: 0.00 AC: 0 AN: 34450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24524

East Asian (EAS) AF: 0.00 AC: 0 AN: 33800

South Asian (SAS) AF: 0.00 AC: 0 AN: 77356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4020

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1071384

Other (OTH) AF: 0.00 AC: 0 AN: 57038

⚠️ 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.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
CardioboostCm	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.062
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.52
Sift	Benign	0.033	D
Sift4G	Uncertain	0.060	T
Polyphen		0.40	B
Vest4		0.45
MutPred		0.23		Loss of MoRF binding (P = 0.018)
MVP		0.84
MPC		1.1
ClinPred		0.86	D
GERP RS		3.9
PromoterAI		0.015	Neutral
Varity_R		0.77
gMVP		0.66
Mutation Taster		=63/37	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs886041517; hg19: chr12-112856925;