rs372736227

Variant names:

• chr12-112446309-A-G
• rs372736227
• NM_002834.5:c.48A>G
• PTPN11 p.Ala16Ala

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACGS-UK Somatic Oncogenicity v2025). B4_Strong

The NM_002834.5(PTPN11):c.48A>G (p.Ala16Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The gene PTPN11 is a tumor suppressor gene (CancerMine: 27 TSG, 73 oncogene, 18 driver citations). The gene PTPN11 is a known oncogene (CancerMine: 27 TSG, 73 oncogene, 18 driver citations). The gene PTPN11 is a cancer driver gene (CancerMine: 27 TSG, 73 oncogene, 18 driver citations). The variant allele was found at a cumulative frequency of 0.00049 (AC=791) in the gnomAD database across 1,614,012 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000753. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★).

• 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:12
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• 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: Orphanet, ClinGen
• metachondromatosis

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

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

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

• B4: Synonymous/intronic variant with confirmed no splicing impact (B4 strong); Synonymous variant — splicing algorithms confirm no impact on splicing (B4 strong [-4])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002834.5. You can select a different transcript below to see updated classification 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

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	0.000296	45	0	152220	32
GnomAD2 exomes	0.000278	70		251442
GnomAD4 exome	0.000510	746	0	1461792	31
GnomAD4 genome	0.000296	45	0	152220	32
TOPMed (Bravo)	0.000249
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.000290	27	0	93102
Local & regional cohorts 3 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	0.000154	2		13006
Turkish Variome	0.000456	3	0	6580
UK10K	0.000397	3		7562

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0000900 *	1	11112	0.0000568 *	1	17618
BipEx(Bipolar disorder (including schizoaffective))	0.000422	12	28420	0.000451	13	28844
Epi25(Epilepsy)	0.000381	16	41958	0.000613	41	66886
SCHEMA(Schizophrenia)	0.000370	45	121676	0.000342	65	190112

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	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

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Uncertain	-	13
BayesDel_noAF	Benign	-	-0.58
CADD	Benign	-	8.7
DANN	Benign	-	0.74
GPN-Star LLR	N/A	-	1.8
GPN-Star score	N/A	-	-1.8
Mutation Taster	N/A	polymorphism	96/4
PhyloP100	Benign	-	-0.033

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs372736227;

hg19: chr12-112884113;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar