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rs1064794276

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001042492.3(NF1):c.3739_3742del(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. L1246L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 31)

Consequence

NF1
NM_001042492.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.52
Variant links:
Genes affected
NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-31235638-CTGTT-C is Pathogenic according to our data. Variant chr17-31235638-CTGTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 420078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31235638-CTGTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NF1NM_001042492.3 linkuse as main transcriptc.3739_3742del p.Phe1247IlefsTer18 frameshift_variant 28/58 ENST00000358273.9
NF1NM_000267.3 linkuse as main transcriptc.3739_3742del p.Phe1247IlefsTer18 frameshift_variant 28/57

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NF1ENST00000358273.9 linkuse as main transcriptc.3739_3742del p.Phe1247IlefsTer18 frameshift_variant 28/581 NM_001042492.3 P1P21359-1

Frequencies

GnomAD3 genomes
Cov.:
31
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:6
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenOct 26, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -
Pathogenic, criteria provided, single submitterclinical testingClinical Molecular Genetics Laboratory, Johns Hopkins All Children's HospitalMay 22, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics, University of ZurichMay 24, 2022- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 01, 2023This 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. -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-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. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 06, 2014- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxJul 17, 2020Frameshift 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 in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 12807981, 18546366, 10712197, 23913538) -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 03, 2019The 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1064794276; hg19: chr17-29562656; API