chr17-31265335-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM5PP2PP3_ModerateBS2_Supporting
The NM_001042492.3(NF1):c.4831C>T(p.Arg1611Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,453,770 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1611Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.4831C>T | p.Arg1611Trp | missense_variant | 36/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.4768C>T | p.Arg1590Trp | missense_variant | 35/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.4831C>T | p.Arg1611Trp | missense_variant | 36/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250500Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135686
GnomAD4 exome AF: 0.00000413 AC: 6AN: 1453770Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2AN XY: 723852
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 11, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2023 | Observed in individuals with suspected neurofibromatosis type 1, some not meeting NIH criteria (Upadhyaya et al., 1997; Evans et al., 2016; Barrea et al., 2018; Stella et al., 2018; Giugliano et al., 2019; Bianchessi et al., 2020; Napolitano et al., 2022); 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: 32680567, 21089070, 9298829, 24803665, 27322474, 16405917, 29471550, 31370276, 32575496, 29673180, 35885913) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 11, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
Neurofibromatosis, type 1 Pathogenic:1Uncertain:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1590 of the NF1 protein (p.Arg1590Trp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 9298829, 27322474, 29673180, 32575496). ClinVar contains an entry for this variant (Variation ID: 404515). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NF1 function (PMID: 21089070). This variant disrupts the p.Arg1590 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Uncertain significance and reported on 02-10-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
NF1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 20, 2023 | The NF1 c.4831C>T variant is predicted to result in the amino acid substitution p.Arg1611Trp. This variant is also referred to as p.Arg1590Trp in an alternate transcript (NM_000267.3). This variant has been reported in individuals with features of neurofibromatosis type 1 (Upadhyaya et al. 1997. PubMed ID: 9298829; Giugliano et al. 2019. PubMed ID: 31370276). However, the variant was also detected in unaffected family members (Evans et al. 2016. PubMed ID: 27322474; Bianchessi et al. 2020. PubMed ID: 32575496). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretations of likely pathogenic and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/404515/). Although we suspect this variant could be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Juvenile myelomonocytic leukemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 29, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at