rs201712827
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_001042492.3(NF1):c.6172A>G(p.Ile2058Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,613,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 0 hom. )
Consequence
NF1
NM_001042492.3 missense
NM_001042492.3 missense
Scores
3
4
12
Clinical Significance
Conservation
PhyloP100: 8.73
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, NF1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.030422658).
BP6
?
Variant 17-31336659-A-G is Benign according to our data. Variant chr17-31336659-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134887.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, not_provided=1, Likely_benign=5, Benign=1}.
BS2
?
High AC in GnomAd at 24 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.6172A>G | p.Ile2058Val | missense_variant | 42/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.6109A>G | p.Ile2037Val | missense_variant | 41/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.6172A>G | p.Ile2058Val | missense_variant | 42/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152008Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
24
AN:
152008
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000839 AC: 21AN: 250150Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135316
GnomAD3 exomes
AF:
AC:
21
AN:
250150
Hom.:
AF XY:
AC XY:
14
AN XY:
135316
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000193 AC: 282AN: 1461322Hom.: 0 Cov.: 34 AF XY: 0.000187 AC XY: 136AN XY: 726918
GnomAD4 exome
AF:
AC:
282
AN:
1461322
Hom.:
Cov.:
34
AF XY:
AC XY:
136
AN XY:
726918
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000158 AC: 24AN: 152008Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74212
GnomAD4 genome
?
AF:
AC:
24
AN:
152008
Hom.:
Cov.:
32
AF XY:
AC XY:
11
AN XY:
74212
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
3
ALSPAC
AF:
AC:
1
ExAC
?
AF:
AC:
13
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 28, 2022 | _x000D_ Criteria applied: PP2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 20, 2019 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. - |
not specified Uncertain:2Benign:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 19, 2017 | The p.Ile2058Val variant in NF1 has not been previously reported in individuals with RASopathies, but has been reported in ClinVar (Variation ID: 134887). It ha s been identified in 22/125856 European chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201712827). Computatio nal prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of t he p.Ile2058Val variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 24, 2020 | DNA sequence analysis of the NF1 gene demonstrated a sequence change, c.6109A>G, in exon 41 that results in an amino acid change, p.Ile2037Val. This sequence change does not appear to have been previously described in patients with NF1-related disorders and has been described in the gnomAD database with a low population frequency of 0.016% in non-Finnish European subpopulation (dbSNP rs201712827). The p.Ile2037Val change affects a moderately conserved amino acid residue located in a domain of the NF1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile2037Val substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile2037Val change remains unknown at this time. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 30, 2022 | Variant summary: NF1 c.6109A>G (p.Ile2037Val) results in a conservative amino acid change which is located outside of any known functional domain or repeat of the encoded protein sequence (InterPro, UniProt). Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250150 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.00021), allowing no conclusion about variant significance. However, the variant is reported with a much higher occurrence in the Amish (i.e. 11/910 alleles; a frequency of 0.012), suggesting that the variant might be a benign polymorphism. The variant, c.6109A>G, has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (Koczkowska_2018) or suspected RASopathy (Witkowski_2020), however in one of these reports the variant was found in a family in the proband, and not found in two affected family members, while all affected family members had a (likely) pathogenic variant, which segregated with the disease phenotype (Koczkowska_2018). In addition, the variant was reported in patients with breast cancer (Dorling_2021), but was also found in healthy controls (Bodian_2014, Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=8) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 27, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 28, 2015 | In silico models in agreement (benign);Other data supporting benign classification - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 08, 2021 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2019 | This variant is associated with the following publications: (PMID: 32107864, 24728327) - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | NF1: PP2, BS1 - |
NF1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 05, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Uncertain
T;.;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;P;.
Vest4
MutPred
Gain of MoRF binding (P = 0.1041);.;.;
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at