rs397516807

Variant names:

• chr12-112455967-TA-T
• rs397516807
• NM_002834.5:c.661delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002834.5(PTPN11):​c.661delA​(p.Ile221fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTPN11 NM_002834.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.88

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]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-112455967-TA-T is Pathogenic according to our data. Variant chr12-112455967-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 44611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.661delA	p.Ile221fs	frameshift_variant	Exon 6 of 16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.661delA	p.Ile221fs	frameshift_variant	Exon 6 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.661delA	p.Ile221fs	frameshift_variant	Exon 6 of 15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metachondromatosis Pathogenic:1

Sep 07, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ile221X variant has not been reported in the literature nor previously ident ified in our laboratory in over 1,800 individuals tested. This variant leads to a premature stop codon at position 221, which is predicted to result in a trunca ted or absent protein. Nonsense variants and other loss-of-function variants hav e been identified as pathogenic in individuals with metachondromatosis (Sobreira 2010, Bowen 2011). Therefore, this variant is highly likely to be pathogenic. The presence of a heterozygous pathogenic loss-of-function variant in PTPN11 is consistent with a diagnosis of metachondromatosis but this information should be reconciled with the complete clinical history of this individual. -

RASopathy Pathogenic:1

Mar 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 44611). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile221*) in the PTPN11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTPN11 are known to be pathogenic (PMID: 20577567, 21533187). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516807; hg19: chr12-112893771;