chr17-31334883-T-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_001042492.3(NF1):c.5858T>C(p.Leu1953Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1953R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.5858T>C | p.Leu1953Pro | missense_variant | 40/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.5795T>C | p.Leu1932Pro | missense_variant | 39/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.5858T>C | p.Leu1953Pro | missense_variant | 40/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 18, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1932 of the NF1 protein (p.Leu1932Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 and/or NF1-related conditions (PMID: 2114220, 12522551, 31776437; Invitae). In at least one individual the variant was observed to be de novo. This variant is also known as 1045C>T. ClinVar contains an entry for this variant (Variation ID: 334). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 02, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 03, 2013 | - - |
not provided Uncertain:1Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 07, 2019 | Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 12522551, 2114220, 31776437) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at