12-112450362-A-T

Position:

• chr12-112450362-A-T

Variant summary

Our verdict is Pathogenic. Variant got 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. D61G) 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

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

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain SH2 1 (size 96) in uniprot entity PTN11_HUMAN there are 61 pathogenic changes around while only 0 benign (100%) 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 chr12-112450362-A-G is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTPN11. . Gene score misZ: 3.1293 (greater than the threshold 3.09). Trascript score misZ: 4.9438 (greater than threshold 3.09). The gene has 131 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. GenCC has associacion of the gene with Noonan syndrome and Noonan-related syndrome, Noonan syndrome with multiple lentigines, metachondromatosis, Noonan syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, LEOPARD syndrome 1, Costello syndrome.
• 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 id is 40496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-112450362-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTPN11	NM_002834.5	c.182A>T	p.Asp61Val	missense_variant	3/16	ENST00000351677.7	NP_002825.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTPN11	ENST00000351677.7	c.182A>T	p.Asp61Val	missense_variant	3/16	1	NM_002834.5	ENSP00000340944.3
PTPN11	ENST00000635625.1	c.182A>T	p.Asp61Val	missense_variant	3/15	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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 26, 2019	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). 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). 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. -

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
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

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

Publications

LitVar

Other links and lift over

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