chr22-29678289-A-G
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1BP4_ModerateBP6BS1BS2
The NM_000268.4(NF2):āc.1540A>Gā(p.Met514Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,614,122 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M514L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000268.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF2 | NM_000268.4 | c.1540A>G | p.Met514Val | missense_variant | 14/16 | ENST00000338641.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF2 | ENST00000338641.10 | c.1540A>G | p.Met514Val | missense_variant | 14/16 | 1 | NM_000268.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152204Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251494Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135920
GnomAD4 exome AF: 0.000122 AC: 178AN: 1461800Hom.: 0 Cov.: 32 AF XY: 0.000124 AC XY: 90AN XY: 727196
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152322Hom.: 1 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74484
ClinVar
Submissions by phenotype
Neurofibromatosis, type 2 Uncertain:6Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces methionine with valine at codon 514 of the NF2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies reported that the variant protein had impaired in vitro binding to the Hippo signaling pathway proteins, Lats1 and AMOTL1 (PMID: 26045165, 33058421). This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 28/282872 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 514 of the NF2 protein (p.Met514Val). This variant is present in population databases (rs201527155, gnomAD 0.02%). This missense change has been observed in individual(s) with bilateral vestibular schwannomas and/or breast cancer (PMID: 16983642, 35264596). ClinVar contains an entry for this variant (Variation ID: 201125). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NF2 function (PMID: 26045165). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 09, 2023 | This missense variant replaces methionine with valine at codon 514 of the NF2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies reported that the variant protein had impaired in vitro binding to the Hippo signaling pathway proteins, Lats1 and AMOTL1 (PMID: 26045165, 33058421). This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. This variant has been identified in 28/282872 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jun 19, 2015 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 13, 2021 | The NF2 c.1540A>G; p.Met514Val variant (rs201527155) is reported in the literature in an individual with bilateral vestibular schwannoma, but was not determined to be causative (Ahronowitz 2007). The variant is reported in the ClinVar database (Variation ID: 201125) and is reported in the general population with an overall allele frequency of 0.0099% (28/282,872 alleles) in the Genome Aggregation Database. The methionine at codon 514 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.656). Due to limited information, the clinical significance of the p.Met514Val variant is uncertain at this time. Gene Statement: References: Ahronowitz I et al. Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings. Hum Mutat. 2007 Jan;28(1):1-12. PMID: 16983642. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2022 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 22, 2021 | - - |
NF2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 22, 2024 | The NF2 c.1540A>G variant is predicted to result in the amino acid substitution p.Met514Val. This variant was reported in an individual with bilateral vestibular schwannomas; however, pathogenicity was not established (Ahronowitz et al 2007. PubMed ID: 16983642). This variant was also reported as a variant of uncertain significance in a large study of Brazilian breast cancer patients (Supp Table 3 in Guindalini RSC et al 2022. PubMed ID: 35264596). This variant is reported in 0.016% of alleles in individuals of European (Finnish) descent in gnomAD, which is likely too common for an autosomal dominant disorder. This variant is reported in ClinVar with conflicting interpretations of uncertain and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/201125/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Familial meningioma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 17, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at