rs267606606
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_001042492.3(NF1):c.2970_2972delAAT(p.Met991del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,504 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
NF1
NM_001042492.3 disruptive_inframe_deletion
NM_001042492.3 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.91
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 13 ACMG points.
PM1
In a helix (size 10) in uniprot entity NF1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001042492.3
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001042492.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 17-31229953-CAAT-C is Pathogenic according to our data. Variant chr17-31229953-CAAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31229953-CAAT-C is described in Lovd as [Pathogenic]. Variant chr17-31229953-CAAT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NF1 | NM_001042492.3 | c.2970_2972delAAT | p.Met991del | disruptive_inframe_deletion | 22/58 | ENST00000358273.9 | NP_001035957.1 | |
| NF1 | NM_000267.3 | c.2970_2972delAAT | p.Met991del | disruptive_inframe_deletion | 22/57 | NP_000258.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NF1 | ENST00000358273.9 | c.2970_2972delAAT | p.Met991del | disruptive_inframe_deletion | 22/58 | 1 | NM_001042492.3 | ENSP00000351015.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250346Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135546
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1459504Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 726064
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:24Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:11Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 26, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 09, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 15, 2016 | The p.Met992del variant in NF1 has been previously reported in >20 individuals w ith NF1, segregated with disease in >20 affected relatives, and was de novo in a t least 1 of these individuals (Upadhyaya 2007, Quintans 2011). Individuals with this variant were reported to not have cutaneous neurofibromas (Upadhyaya 2007, Quintans 2011). This variant has also been reported in ClinVar (Variation ID: 3 63) and has been identified in 1/66338 European chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org). This variant is a deleti on of 1 amino acid at position 992 and is not predicted to alter the protein rea ding frame. In summary, this variant meets our criteria to be classified as path ogenic for NF1 in an autosomal dominant manner based upon frequency in probands and segregation studies. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been previously reported as de novo in a similarly affected individual (PMID: 30190611) and observed in multiple (>3) similarly affected unrelated individuals (PMID:23656349, 30190611, 30308447). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics, University of Zurich | May 10, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2020 | Variant summary: NF1 c.2970_2972delAAT (p.Met992del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4e-06 in 250346 control chromosomes. c.2970_2972delAAT has been reported in the literature in a large number of individuals affected with NF1 Related Conditions (e.g. Stevenson_2006, Tsipi_2018, Koczkowska_2019). These data indicate that the variant is very likely to be associated with disease. A study on 135 individuals carrying this variant showed that these individuals have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas (Koczkowska_2019). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 24, 2023 | This variant, c.2970_2972del, results in the deletion of 1 amino acid(s) of the NF1 protein (p.Met992del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs267606606, gnomAD no frequency). This variant has been observed in individual(s) with clinical features of NF1-related conditions (PMID: 7904209, 12807981, 17160901, 20602485, 21532985, 23047742). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 363). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Medical Genetics, University of Parma | Dec 20, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | May 08, 2023 | PS4, PM2, PM4, PM6_Strong, PP1_Strong - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 22, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 05, 2022 | In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26740943, 26056819, 25329635, 26345759, 12807981, 25074460, 26962827, 27920686, 28213670, 27785414, 27322453, 10712197, 10862084, 7904209, 14569132, 16380919, 16542390, 20602485, 23047742, 26457592, 25966637, 16944272, 18546366, 23656349, 25370043, 23972508, 17160901, 26178382, 24232412, 26979265, 26956402, 27838393, 30190611, 30109123, 1568246, 29968256, 31717729, 31776437, 21532985, 31370276, 32107864, 25486365, 2121369) - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 06, 2021 | The NF1 c.2970_2972delAAT; p.Met992del variant (rs267606606) is reported in the literature in several unrelated individuals and families affected with a milder form of neurofibromatosis type 1 (NF1), characterized by a lack of neurofibromas (Kehrer-Sawatzki 2015, Koczkowska 2019, Quintans 2011, Upadhyaya 2007). This variant is also reported in ClinVar (Variation ID: 363). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single methionine residue leaving the rest of the protein in-frame. Based on available information, information, this variant is considered to be pathogenic. References: Kehrer-Sawatzki H et al. Neurofibromatosis Type 1 Without Neurofibromas: Genotype-Phenotype Correlations in NF1. Hum Mutat. 2015 Nov;36(11):v. Koczkowska M et al. Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation. Genet Med. 2019 Apr;21(4):867-876. Quintans B et al. Neurofibromatosis without Neurofibromas: Confirmation of a Genotype-Phenotype Correlation and Implications for Genetic Testing. Case Rep Neurol. 2011 Apr 11;3(1):86-90. Upadhyaya M et al. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007 Jan;80(1):140-51. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 23, 2022 | PP1_strong, PM2, PM6, PS4_moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Jan 16, 2018 | - - |
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
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 28, 2021 | - - |
Neurofibromatosis-Noonan syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
Juvenile myelomonocytic leukemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 26, 2021 | - - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Café-au-lait macules with pulmonary stenosis Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2015 | ​The c.2970_2972delAAT pathogenic mutation (also known as p.M992del and delM992) is located in coding exon 22 of the NF1 gene. This alteration results from an in-frame AAT deletion between nucleotide positions 2970 and 2972. This results in the deletion of a highly conserved methionine residue at codon992. This alteration was first identified in two unrelated probands with paternally inherited neurofibromatosis type 1 (NF1) (Shen MH et al. Hum Mol Genet. 1993; 2(11):1861-4). Later studies suggest this mutation is associated with an attenuated form of NF1 similar to Legious syndrome; individuals with this mutation are not likely to develop neurofibromas (Upadhyaya M et al. Am J Hum Genet. 2007; 80(1):140-51). Based on the supporting evidence, c.2970_2972delAAT is interpreted as a disease-causing mutation. - |
Computational scores
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Details are displayed if max score is > 0.2
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