chr12-112419124-A-C

Variant names:

• chr12-112419124-A-C
• rs587781133
• NM_002834.5:c.13A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002834.5(PTPN11):​c.13A>C​(p.Arg5Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,371,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R5R) has been classified as Uncertain significance. The gene PTPN11 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: PTPN11 NM_002834.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• Publications: 0 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

ACMG classification

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.13A>C	p.Arg5Arg	splice_region synonymous	Exon 1 of 16	NP_002825.3
	PTPN11	NM_001330437.2		c.13A>C	p.Arg5Arg	splice_region synonymous	Exon 1 of 16	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.13A>C	p.Arg5Arg	splice_region synonymous	Exon 1 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.13A>C	p.Arg5Arg	splice_region synonymous	Exon 1 of 16	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.13A>C	p.Arg5Arg	splice_region synonymous	Exon 1 of 15	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000392597.5	TSL:1	c.13A>C	p.Arg5Arg	splice_region synonymous	Exon 1 of 11	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1371084 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 676506

African (AFR) AF: 0.00 AC: 0 AN: 28586

American (AMR) AF: 0.00 AC: 0 AN: 34200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24446

East Asian (EAS) AF: 0.00 AC: 0 AN: 33434

South Asian (SAS) AF: 0.00 AC: 0 AN: 77086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4010

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1070186

Other (OTH) AF: 0.00 AC: 0 AN: 56926

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Benign	0.96
PhyloP100		1.6
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.12		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: rs587781133; hg19: chr12-112856928;