rs41304351

Variant names:

• chr12-112453399-G-C
• rs41304351
• NM_002834.5:c.525+12G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.525+12G>C variant in the PTPN11 gene is 1.4% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (969/66644 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additional case level data available: SCV000057399.8; SCV000061311.5; SCV000248623.2; SCV000206755.1; SCV000207666.1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA134671/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.010 (17 hom., cov: 32)
  • Exomes 𝑓: 0.013 (147 hom.)
• Consequence: PTPN11 NM_002834.5 intron
• Clinical Significance: Benign reviewed by expert panel B:19
• Conservation: PhyloP100: -1.29
• Publications: 4 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

ENSG00000305447 (HGNC:):

ACMG classification

Specifications for PTPN11 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.525+12G>C		intron	N/A	NP_002825.3
	PTPN11	NM_001330437.2		c.525+12G>C		intron	N/A	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.522+12G>C		intron	N/A	NP_001361554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.525+12G>C		intron	N/A	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.525+12G>C		intron	N/A	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000392597.5	TSL:1	c.525+12G>C		intron	N/A	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1563 AN: 152204 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0100 AC: 2522 AN: 251322 AF XY: 0.0101

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0134 AC: 19579 AN: 1461052 Hom.: 147 Cov.: 31 AF XY: 0.0130 AC XY: 9453 AN XY: 726856

African (AFR) AF: 0.00164 AC: 55 AN: 33462

American (AMR) AF: 0.0143 AC: 641 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 211 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00199 AC: 172 AN: 86240

European-Finnish (FIN) AF: 0.00281 AC: 150 AN: 53414

Middle Eastern (MID) AF: 0.00360 AC: 20 AN: 5550

European-Non Finnish (NFE) AF: 0.0158 AC: 17540 AN: 1111494

Other (OTH) AF: 0.0131 AC: 789 AN: 60352

GnomAD4 genome AF: 0.0102 AC: 1560 AN: 152322 Hom.: 17 Cov.: 32 AF XY: 0.00960 AC XY: 715 AN XY: 74484

African (AFR) AF: 0.00267 AC: 111 AN: 41578

American (AMR) AF: 0.0218 AC: 334 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1022 AN: 68036

Other (OTH) AF: 0.0147 AC: 31 AN: 2116

Alfa AF: 0.0113 Hom.: 2

Bravo AF: 0.0117

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	2	Metachondromatosis (2)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Juvenile myelomonocytic leukemia (1)
-	-	1	LEOPARD syndrome 1 (1)
-	-	1	Noonan syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.22
DANN	Benign	0.48
PhyloP100		-1.3
PromoterAI		0.0076	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs41304351; hg19: chr12-112891203;