chr12-112471592-T-C

Variant names:

• chr12-112471592-T-C
• rs11066321
• NM_002834.5:c.757-1352T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002834.5(PTPN11):​c.757-1352T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 152,130 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.039 (263 hom., cov: 31)
• Consequence: PTPN11 NM_002834.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 5 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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

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.757-1352T>C		intron	N/A	NP_002825.3
	PTPN11	NM_001330437.2		c.757-1352T>C		intron	N/A	NP_001317366.1	Q06124-1
	PTPN11	NM_001374625.1		c.754-1352T>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.757-1352T>C		intron	N/A	ENSP00000340944.3	Q06124-2
	PTPN11	ENST00000635625.1	TSL:5	c.757-1352T>C		intron	N/A	ENSP00000489597.1	Q06124-1
	PTPN11	ENST00000392597.5	TSL:1	c.757-1352T>C		intron	N/A	ENSP00000376376.1	Q06124-3

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5912 AN: 152012 Hom.: 261 Cov.: 31

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0237

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00828

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0325

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0390 AC: 5930 AN: 152130 Hom.: 263 Cov.: 31 AF XY: 0.0376 AC XY: 2794 AN XY: 74386

African (AFR) AF: 0.108 AC: 4484 AN: 41506

American (AMR) AF: 0.0236 AC: 360 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00849 AC: 44 AN: 5182

South Asian (SAS) AF: 0.00912 AC: 44 AN: 4826

European-Finnish (FIN) AF: 0.0106 AC: 112 AN: 10546

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0117 AC: 797 AN: 68002

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0345 Hom.: 34

Bravo AF: 0.0435

Asia WGS AF: 0.0160 AC: 55 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.7
DANN	Benign	0.81
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs11066321; hg19: chr12-112909396;