12-112450355-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_002834.5(PTPN11):c.175A>G(p.Thr59Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,160 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PTPN11 | ENST00000351677.7 | c.175A>G | p.Thr59Ala | missense_variant | Exon 3 of 16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
PTPN11 | ENST00000635625.1 | c.175A>G | p.Thr59Ala | missense_variant | Exon 3 of 15 | 5 | ENSP00000489597.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250992Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135626
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460974Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726834
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74344
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
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Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 31324109, 34315577, 37595579, 19020799, 11992261, 9491886, 16053901, 29493581) -
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
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RASopathy Pathogenic:1
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 59 of the PTPN11 protein (p.Thr59Ala). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19020799, 31324109). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 288033). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
PTPN11-related disorder Uncertain:1
The PTPN11 c.175A>G variant is predicted to result in the amino acid substitution p.Thr59Ala. This variant has been reported in individuals with Noonan syndrome (Ko et al. 2008. PubMed ID: 19020799; Matyášová et al. 2019. PubMed ID: 31324109). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-112888159-A-G). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Cardiovascular phenotype Uncertain:1
The c.175A>G (p.T59A) alteration is located in exon 3 (coding exon 3) of the PTPN11 gene. This alteration results from a A to G substitution at nucleotide position 175, causing the threonine (T) at amino acid position 59 to be replaced by an alanine (A). Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/250992) total alleles studied. The highest observed frequency was 0.006% (1/16256) of African alleles. This variant has been determined to be the result of a de novo mutation in one individual with features consistent with PTPN11-related RASopathy (Ko, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at