17-31232852-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP2PP3_ModeratePP5
The NM_001042492.3(NF1):c.3467A>G(p.Asn1156Ser) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N1156N) has been classified as Benign.
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
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251354Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135840
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461854Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727230
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:3
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1156 of the NF1 protein (p.Asn1156Ser). This variant is present in population databases (rs199474764, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features consistent with neurofibromatosis, type 1 (PMID: 10712197, 24789688; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 68332). 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 NF1 protein function with a positive predictive value of 95%. This variant disrupts the p.Asn1156 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). 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. -
Criteria applied: PVS1(RNA),PS4_MOD,PM2 -
Variant summary: NF1 c.3467A>G (p.Asn1156Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a cryptic exonic 3' acceptor site. Two predict the variant creates an alternate cryptic exonic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251354 control chromosomes. c.3467A>G has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (e.g. Xu_2014, Fahsold_2020), although a congruence to NF1 pseudogene sequence was reported in at-least one of these reports (Fahsold_2020). Additionally, this variant has been observed in multiple cases with clinical features of Neurofibromatosis, Type 1 tested at our laboratory and data shared by the NF1 VCEP group, University of Alabama (personal correspondence). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10712197, 31617914, 24789688). ClinVar contains an entry for this variant (Variation ID: 68332). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:1Uncertain:1Other:1
Not observed at significant frequency in large population cohorts (gnomAD); 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: 31617914, 24789688, 24803665, 25074460, 10712197, 34449562, 25486365, 2121369, 22807134) -
PP2, PP5, PS4 -
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Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:1
PM2_Supporting+PP2+PS4_Moderate+PP4+PM6_Supporting -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
The p.N1156S variant (also known as c.3467A>G), located in coding exon 26 of the NF1 gene, results from an A to G substitution at nucleotide position 3467. The asparagine at codon 1156 is replaced by serine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (NF1) and has been identified de novo in several cases (Xu W et al. Int J Mol Med, 2014 Jul;34:53-60; Fahsold R et al. Am. J. Hum. Genet. 2000; 66:790-818; Togi S et al. Curr Issues Mol Biol, 2021 Jul;43:782-801; external communication). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
not specified Uncertain:1
The NF1 c.3467A>G; p.Asn1156Ser variant (rs199474764) has been described in individuals affected with neurofibromatosis type 1 (NF1; Fahsold 2000, Xu 2014). It is observed on only one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 1156 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Additionally, computational splicing programs (Alamut v.2.11) predict that this variant impacts splicing by creating a cryptic splice acceptor site, and analysis of mRNA from peripheral blood of an individual harboring this variant demonstrated aberrant splicing leading to exon skipping (Xu 2014). However, this study did not quantify the amount of incorrectly spliced transcript. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. REFERNECES Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Xu W et al. Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing. Int J Mol Med. 2014 Jul;34(1):53-60. -
Juvenile myelomonocytic leukemia Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at