chr12-112446309-A-G

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -17 classification points (ACMG Germline Pathogenicity v2019). BS2BP4_StrongBP6_Very_StrongBP7

The NM_002834.5(PTPN11):c.48A>G (p.Ala16Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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 ACMG Germline Pathogenicity v2019

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

Classification was made for transcript:

Our verdict: Benign. The variant received -17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 3 star(s). ClinVar submissions strongly and reliably favor benignity (12/14 total B/LB).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).
	BS2Observed in healthy adult		Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 0.; Very high cumulative gnomAD AC = 791 (any gene).

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	Prot: NP_002825.3
	PTPN11 NM_001330437.2		c.48A>G p.Ala16Ala	synonymous	Exon 2 of 16	Prot: NP_001317366.1 UniProt:
	PTPN11 NM_001374625.1		c.48A>G p.Ala16Ala	synonymous	Exon 2 of 16	Prot: NP_001361554.1

PTPN11 NM_002834.5

MANE Select

HGVSc / HGVSpc.48A>Gp.Ala16Ala

Exon rankExon 2 of 16

synonymous

Prot: NP_002825.3

PTPN11 NM_001330437.2

HGVSc / HGVSpc.48A>Gp.Ala16Ala

Exon rankExon 2 of 16

synonymous

Prot: NP_001317366.1UniProt: Q06124-1

PTPN11 NM_001374625.1

HGVSc / HGVSpc.48A>Gp.Ala16Ala

Exon rankExon 2 of 16

synonymous

Prot: NP_001361554.1

Ensembl Transcripts

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

PTPN11 ENST00000351677.7

TSL:1MANE Select

HGVSc / HGVSpc.48A>Gp.Ala16Ala

Exon rankExon 2 of 16

synonymous

Prot: ENSP00000340944.3UniProt: Q06124-2

PTPN11 ENST00000635625.1

TSL:5

HGVSc / HGVSpc.48A>Gp.Ala16Ala

Exon rankExon 2 of 15

synonymous

Prot: ENSP00000489597.1UniProt: Q06124-1

PTPN11 ENST00000392597.5

TSL:1

HGVSc / HGVSpc.48A>Gp.Ala16Ala

Exon rankExon 2 of 11

synonymous

Prot: ENSP00000376376.1UniProt: 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	AF: 0.000296	AC:45	Hom:0	AN:152220	Cov:32
GnomAD2 exomes	AF: 0.000278	AC:70	Hom:	AN:251442	Cov:
GnomAD4 exome	AF: 0.000510	AC:746	Hom:0	AN:1461792	Cov:31
GnomAD4 genome	AF: 0.000296	AC:45	Hom:0	AN:152220	Cov:32
TOPMed (Bravo)	AF: 0.000249	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000290	AC:27	Hom:0	AN:93102	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000154	AC:2	Hom:	AN:13006	Cov:
Turkish Variome	AF: 0.000456	AC:3	Hom:0	AN:6580	Cov:
UK10K	AF: 0.000397	AC:3	Hom:	AN:7562	Cov:

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 pred.	Score	Prediction
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	96/4	polymorphism
PhyloP100	Benign	-0.033

Showing 8 of 8 scores

Splicing Scores

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

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs372736227;

hg19: chr12-112884113;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar