12-112419121-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2PM5PP2PP5BP4

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

Scores

4
9
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 3.40

Publications

2 publications found
Variant links:
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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
  • Noonan syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • Noonan syndrome 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
  • Noonan syndrome with multiple lentigines
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • metachondromatosis
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
  • cardiofaciocutaneous syndrome
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
  • Costello syndrome
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id 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 id is 280283.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
BP4
Computational evidence support a benign effect (MetaRNN=0.40868947). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTPN11NM_002834.5 linkc.10C>G p.Arg4Gly missense_variant Exon 1 of 16 ENST00000351677.7 NP_002825.3 Q06124-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTPN11ENST00000351677.7 linkc.10C>G p.Arg4Gly missense_variant Exon 1 of 16 1 NM_002834.5 ENSP00000340944.3 Q06124-2
PTPN11ENST00000635625.1 linkc.10C>G p.Arg4Gly missense_variant Exon 1 of 15 5 ENSP00000489597.1 Q06124-1

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
show subpopulations
⚠️ 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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.400
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Nov 08, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36760995, 34918830, 9491886, 11992261, 16053901, 29493581) -

Aug 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;D;D;D
M_CAP
Pathogenic
0.97
D
MetaRNN
Benign
0.41
T;T;T;T
MetaSVM
Uncertain
0.79
D
MutationAssessor
Uncertain
2.3
M;M;.;M
PhyloP100
3.4
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-1.7
N;N;.;.
REVEL
Uncertain
0.52
Sift
Benign
0.033
D;D;.;.
Sift4G
Uncertain
0.060
T;D;.;D
Polyphen
0.40
B;B;.;.
Vest4
0.45
MutPred
0.23
Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);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

Publications

Other links and lift over

dbSNP: rs886041517; hg19: chr12-112856925; API