rs1064794276
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.3739_3742delTTTG(p.Phe1247IlefsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F1247F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001042492.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NF1 | NM_001042492.3 | c.3739_3742delTTTG | p.Phe1247IlefsTer18 | frameshift_variant | Exon 28 of 58 | ENST00000358273.9 | NP_001035957.1 | |
| NF1 | NM_000267.3 | c.3739_3742delTTTG | p.Phe1247IlefsTer18 | frameshift_variant | Exon 28 of 57 | NP_000258.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:7
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This sequence change creates a premature translational stop signal (p.Phe1247Ilefs*18) in the NF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type I (PMID: 10712197, 18546366). ClinVar contains an entry for this variant (Variation ID: 420078). For these reasons, this variant has been classified as Pathogenic. -
Neurofibromatosis Type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene located at chromosome 17q11.2. This condition is characterized by highly recognizable clinical features, including cutaneous café-au-lait macules, multiple neurofibromas, Lisch nodules of the iris, and optic pathway gliomas, with potential multisystem involvement affecting the skin, nervous system, bones, gastrointestinal tract, and cardiovascular system. In this case, a heterozygous variant in the NF1 gene (c.3739_3742del, p.Phe1247Ilefs*18) was identified, representing a frameshift mutation. This variant involves a deletion of nucleotides at positions 3739–3742 in the NF1 gene, resulting in the substitution of phenylalanine at position 1247 with isoleucine and the introduction of a premature stop codon 18 amino acids downstream. This leads to truncated protein synthesis, affecting protein structure and function. The variant is located in exon 28, within the GRD functional region, which strongly supports its pathogenic potential. According to the ACMG variant classification guidelines, this variant is classified as "pathogenic." Although Sanger sequencing of parental peripheral blood did not detect the c.3739_3742del variant, the possibility of low-level mosaicism in either parent cannot be entirely excluded, indicating that this is a de novo mutation in the proband. -
The frameshift c.3739_3742delp.Phe1247IlefsTer18 variant in NF1 gene has been reported in heterozygous state in multiple individuals affected with neurofibromatosis type 1 Tang J, et. al., 2022; Pemov, A., et al., 2010; Ars E, et. al., 2003. The p.Phe1247IlefsTer18 variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. This variant causes a frameshift starting with codon Phenylalanine 1247, changes this amino acid to Isoleucine residue, and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Phe1247IlefsTer18. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:2
PP4, PM2, PS4_moderate, PVS1 -
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.3737_3740delTGTT; This variant is associated with the following publications: (PMID: 18546366, 23913538, 12807981, 10712197, 36612057) -
Inborn genetic diseases Pathogenic:1
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Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
The c.3739_3742delTTTG pathogenic mutation, located in coding exon 28 of the NF1 gene, results from a deletion of 4 nucleotides between nucleotide positions 3739 and 3742, causing a translational frameshift with a predicted alternate stop codon (p.F1247Ifs*18). This mutation has been reported in two individuals with features suggestive of neurofibromatosis type 1 (NF1), at least one of whom met clinical diagnostic criteria for NF1 (Fahsold R et al. Am. J. Hum. Genet. 2000 Mar; 66(3):790-818. Ars E et al. J. Med. Genet. 2003 Jun; 40(6):e82). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at