rs397516800
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2
The NM_002834.5(PTPN11):c.1746C>T(p.Asn582Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,593,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_002834.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTPN11 | NM_002834.5 | c.1746C>T | p.Asn582Asn | synonymous_variant | Exon 15 of 16 | ENST00000351677.7 | NP_002825.3 | |
PTPN11 | NM_001330437.2 | c.1758C>T | p.Asn586Asn | synonymous_variant | Exon 15 of 16 | NP_001317366.1 | ||
PTPN11 | NM_001374625.1 | c.1743C>T | p.Asn581Asn | synonymous_variant | Exon 15 of 16 | NP_001361554.1 | ||
PTPN11 | XM_011538613.3 | c.1755C>T | p.Asn585Asn | synonymous_variant | Exon 15 of 16 | XP_011536915.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PTPN11 | ENST00000351677.7 | c.1746C>T | p.Asn582Asn | synonymous_variant | Exon 15 of 16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
PTPN11 | ENST00000635625.1 | c.1758C>T | p.Asn586Asn | synonymous_variant | Exon 15 of 15 | 5 | ENSP00000489597.1 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000104 AC: 26AN: 250916Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135586
GnomAD4 exome AF: 0.0000999 AC: 144AN: 1441108Hom.: 0 Cov.: 30 AF XY: 0.000111 AC XY: 80AN XY: 718110
GnomAD4 genome AF: 0.000138 AC: 21AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74326
ClinVar
Submissions by phenotype
not specified Benign:3
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p.Asn582Asn in exon 15 of PTPN11: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 4/15702 South As ian chromosomes and 8/63828 European chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516800 ). Furthermore, it has been identified by our laboratory in an unaffected mother and 2 individuals with features of Noonan syndrome, one of which also carried another variant in PTPN11 sufficient to explain their disease. -
Variant summary: PTPN11 c.1746C>T results in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0001 in 250916 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome and Related Conditions phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1746C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:2
PTPN11: BP4, BP7 -
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Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
RASopathy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at