rs372736227

Variant names:

• chr12-112446309-A-G
• rs372736227
• NM_002834.5:c.48A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.48A>G (p.Ala16=) variant in the PTPN11 gene is 0.0284% (9/16512) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA134668/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: PTPN11 NM_002834.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:11
• Conservation: PhyloP100: -0.0330
• Publications: 2 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• metachondromatosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: 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.48A>G	p.Ala16Ala	synonymous	Exon 2 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.48A>G	p.Ala16Ala	synonymous	Exon 2 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.48A>G	p.Ala16Ala	synonymous	Exon 2 of 16	NP_001361554.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN11	ENST00000351677.7	TSL:1 MANE Select	c.48A>G	p.Ala16Ala	synonymous	Exon 2 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.48A>G	p.Ala16Ala	synonymous	Exon 2 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000392597.5	TSL:1	c.48A>G	p.Ala16Ala	synonymous	Exon 2 of 11	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000278 AC: 70 AN: 251442 AF XY: 0.000324

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000510 AC: 746 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.000535 AC XY: 389 AN XY: 727206

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.0000894 AC: 4 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000553 AC: 615 AN: 1111952

Other (OTH) AF: 0.000745 AC: 45 AN: 60382

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74368

African (AFR) AF: 0.000121 AC: 5 AN: 41460

American (AMR) AF: 0.000262 AC: 4 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.000249

EpiCase AF: 0.000654

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	Metachondromatosis (2)
-	-	2	RASopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LEOPARD syndrome 1 (1)
-	1	-	Noonan syndrome 1 (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.7
DANN	Benign	0.74
PhyloP100		-0.033
Mutation Taster		=96/4	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: rs372736227; hg19: chr12-112884113;