GeneBe

rs28933386

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PP1_StrongPP2PP3PM2PS2PS3

This summary comes from the ClinGen Evidence Repository: The c.922A>G (p.Asn308Asp) variant in PTPN11 has been reported in the literature as a confirmed and unconfirmed de novo occurrence in 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 20979190, and 11704759, 22465605). The variant has co-segregated with disease in more than 7 family members (PP1_Strong; PMID:11992261). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn308Asp variant may impact the protein (PP3). Additionally, at least 2 functional studies have been concordant in showing that this variant may be deleterious to the protein (PS3; PMID 14974085, 15987685, 19509418, 20308328). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM2, PP1_Strong, PS2_VeryStrong, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220158/MONDO:0018997/004

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PTPN11
NM_001330437.2 missense

Scores

12
6
1

Clinical Significance

Pathogenic reviewed by expert panel P:80O:3

Conservation

PhyloP100: 8.89

Publications

166 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

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PS2
For more information check the summary or visit ClinGen Evidence Repository.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP2
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330437.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PTPN11
NM_002834.5
MANE Select
c.922A>Gp.Asn308Asp
missense
Exon 8 of 16NP_002825.3
PTPN11
NM_001330437.2
c.922A>Gp.Asn308Asp
missense
Exon 8 of 16NP_001317366.1
PTPN11
NM_001374625.1
c.919A>Gp.Asn307Asp
missense
Exon 8 of 16NP_001361554.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PTPN11
ENST00000351677.7
TSL:1 MANE Select
c.922A>Gp.Asn308Asp
missense
Exon 8 of 16ENSP00000340944.3
PTPN11
ENST00000635625.1
TSL:5
c.922A>Gp.Asn308Asp
missense
Exon 8 of 15ENSP00000489597.1
PTPN11
ENST00000392597.5
TSL:1
c.922A>Gp.Asn308Asp
missense
Exon 8 of 11ENSP00000376376.1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251440
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.000163
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1460034
Hom.:
0
Cov.:
32
AF XY:
0.00000964
AC XY:
7
AN XY:
726478
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33428
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.0000766
AC:
2
AN:
26122
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86222
European-Finnish (FIN)
AF:
0.0000374
AC:
2
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5758
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1110340
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60338
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.443
Heterozygous variant carriers
0
1
3
4
6
7
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
AF:
0.00000657
AC:
1
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74334
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41442
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68026
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
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

Genome 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
Alfa
AF:
0.0000119
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

ClinVar submissions as Germline
Significance:Pathogenic
Revision:reviewed by expert panel
View on ClinVar

Computational scores

Publications

Other links and lift over

dbSNP: rs28933386; hg19: chr12-112915523; COSMIC: COSV61006575; COSMIC: COSV61006575; API