rs12301915

Positions:

• chr12-112482065-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002834.5(PTPN11):​c.1093-9C>A variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.006815
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.853

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]

ACMG classification

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/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.1093-9C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.1093-9C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002834.5	ENSP00000340944	A1

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5934 AN: 152096 Hom.: 262 Cov.: 32

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

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

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

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:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 20, 2007	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2019	- -
Benign, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	- -

RASopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Metachondromatosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Noonan syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 05, 2021

- -

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

Other links and lift over

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