NM_002834.5:c.1093-9C>A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_002834.5(PTPN11):​c.1093-9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,558,590 control chromosomes in the GnomAD database, including 577 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 264 hom., cov: 32)
Exomes 𝑓: 0.014 ( 313 hom. )

Consequence

PTPN11
NM_002834.5 intron

Scores

2
Splicing: ADA: 0.006815
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 0.853
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.29).
BP6
Variant 12-112482065-C-A is Benign according to our data. Variant chr12-112482065-C-A is described in ClinVar as [Benign]. Clinvar id is 40542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112482065-C-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTPN11NM_002834.5 linkc.1093-9C>A intron_variant Intron 9 of 15 ENST00000351677.7 NP_002825.3 Q06124-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTPN11ENST00000351677.7 linkc.1093-9C>A intron_variant Intron 9 of 15 1 NM_002834.5 ENSP00000340944.3 Q06124-2
PTPN11ENST00000635625.1 linkc.1093-9C>A intron_variant Intron 9 of 14 5 ENSP00000489597.1 Q06124-1
PTPN11ENST00000635652.1 linkc.85-9C>A intron_variant Intron 1 of 4 3 ENSP00000489541.1 A0A0U1RRI0

Frequencies

GnomAD3 genomes
AF:
0.0390
AC:
5934
AN:
152096
Hom.:
262
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.108
Gnomad AMI
AF:
0.00439
Gnomad AMR
AF:
0.0237
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.00828
Gnomad SAS
AF:
0.00953
Gnomad FIN
AF:
0.0111
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.0117
Gnomad OTH
AF:
0.0325
GnomAD3 exomes
AF:
0.0181
AC:
4555
AN:
251222
Hom.:
130
AF XY:
0.0160
AC XY:
2177
AN XY:
135818
show subpopulations
Gnomad AFR exome
AF:
0.118
Gnomad AMR exome
AF:
0.0141
Gnomad ASJ exome
AF:
0.00278
Gnomad EAS exome
AF:
0.00962
Gnomad SAS exome
AF:
0.00970
Gnomad FIN exome
AF:
0.0141
Gnomad NFE exome
AF:
0.0109
Gnomad OTH exome
AF:
0.0168
GnomAD4 exome
AF:
0.0139
AC:
19496
AN:
1406376
Hom.:
313
Cov.:
31
AF XY:
0.0134
AC XY:
9417
AN XY:
702406
show subpopulations
Gnomad4 AFR exome
AF:
0.114
Gnomad4 AMR exome
AF:
0.0148
Gnomad4 ASJ exome
AF:
0.00267
Gnomad4 EAS exome
AF:
0.00531
Gnomad4 SAS exome
AF:
0.00991
Gnomad4 FIN exome
AF:
0.0133
Gnomad4 NFE exome
AF:
0.0114
Gnomad4 OTH exome
AF:
0.0197
GnomAD4 genome
AF:
0.0391
AC:
5952
AN:
152214
Hom.:
264
Cov.:
32
AF XY:
0.0377
AC XY:
2805
AN XY:
74420
show subpopulations
Gnomad4 AFR
AF:
0.108
Gnomad4 AMR
AF:
0.0236
Gnomad4 ASJ
AF:
0.00288
Gnomad4 EAS
AF:
0.00849
Gnomad4 SAS
AF:
0.00933
Gnomad4 FIN
AF:
0.0111
Gnomad4 NFE
AF:
0.0117
Gnomad4 OTH
AF:
0.0326
Alfa
AF:
0.0188
Hom.:
106
Bravo
AF:
0.0435
EpiCase
AF:
0.00905
EpiControl
AF:
0.00960

ClinVar

Significance: Benign
Submissions summary: Benign:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8
-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 20, 2019
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 01, 2013
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 20, 2007
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 15, 2015
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Metachondromatosis Benign:2
Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2
Nov 07, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

RASopathy Benign:2
-
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Noonan syndrome 1 Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

LEOPARD syndrome 1 Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Juvenile myelomonocytic leukemia Benign:1
Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Noonan syndrome and Noonan-related syndrome Benign:1
Jul 05, 2021
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.29
CADD
Benign
15
DANN
Benign
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0068
dbscSNV1_RF
Benign
0.11
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs12301915; hg19: chr12-112919869; COSMIC: COSV61006781; API