12-112450362-A-T

Variant names:

• chr12-112450362-A-T
• rs121918461
• NM_002834.5:c.182A>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002834.5(PTPN11):​c.182A>T​(p.Asp61Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D61Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTPN11 NM_002834.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.31
• Publications: 218 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• metachondromatosis

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 26 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002834.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-112450361-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228392.
• PP2: Missense variant in the PTPN11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 3.1293 (above the threshold of 3.09). Trascript score misZ: 4.9438 (above the threshold of 3.09). GenCC associations: The gene is linked to Costello syndrome, Noonan syndrome 1, Noonan syndrome, LEOPARD syndrome 1, cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, metachondromatosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 12-112450362-A-T is Pathogenic according to our data. Variant chr12-112450362-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 40496.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.182A>T	p.Asp61Val	missense_variant	Exon 3 of 16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.182A>T	p.Asp61Val	missense_variant	Exon 3 of 16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.182A>T	p.Asp61Val	missense_variant	Exon 3 of 15	5		ENSP00000489597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461050 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726854

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111300

Other (OTH) AF: 0.00 AC: 0 AN: 60356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RASopathy Pathogenic:2

Nov 07, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PTPN11 c.182A>T (p.Asp61Val) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251014 control chromosomes. c.182A>T has been reported in the literature in individuals affected with Noonan Syndrome, as well as patients with JMML, AML, and other Noonan syndrome-related phenotypes (ie. Mohan_2022, Tartaglia_2004, Kratz_2005, etc). D61V confers a gain of function to the Ptpn11 protein as demonstrated by increased macrophage progenitor proliferation and colony formation (Chan_2005), hypersensitivity to ligand stimulation and increased Erk phosphorylation (Chan_2005), and elevated basal phosphatase activity in cultured cells (PMID: 30375388). Several other variants affecting the same codon have been reported as pathogenic/likely pathogenic (p.Asp61Asn, p.Asp61Tyr, p.Asp61His, p.Asp61Gly, p.Asp61Ala). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 26, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with valine at codon 61 of the PTPN11 protein (p.Asp61Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant has been observed in several patients affected with acute myeloid leukemia, myelodysplastic syndrome, and juvenile myelomonocytic leukemia (JMML) (PMID: 14982869, 12717436, 25097206, 18470943, 15928039, 23832011). It has also been observed to be de novo in an individual with clinical features consistent with a PTPN11-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 40496). For these reasons, this variant has been classified as Pathogenic. The p.Asp61 amino acid residue in PTPN11 has been determined to be clinically significant (PMID: 25039348, 15521065, 11992261, 26242988, 24803665, 27521173, 20112233, 24803665, 11704759, 15273746, 24718990, 26242988, 15987685, 24803665, 16377799, 19835954, 25383899, 28366775, 24628801, 22371576, 27521173, 19008228, 20651068, 19927903). This suggests that variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change demonstrates hypersensitivity to granulocyte-macrophage colony-stimulating factor leading to sustained phospho-Erk activation (PMID: 17053061, 15644411). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostCm	Uncertain	0.86
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	.;.;.;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;M;.;M
PhyloP100		9.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.4	D;D;.;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;.;D
Polyphen		1.0	D;D;.;.
Vest4		0.98
MutPred		0.84		Loss of phosphorylation at Y63 (P = 0.0817);Loss of phosphorylation at Y63 (P = 0.0817);Loss of phosphorylation at Y63 (P = 0.0817);Loss of phosphorylation at Y63 (P = 0.0817);
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.86
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs121918461; hg19: chr12-112888166; COSMIC: COSV61004983; COSMIC: COSV61004983;