ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.7970+4_7970+7del

dbSNP: rs1064794279
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483040 SCV000568617 uncertain significance not provided 2016-12-23 criteria provided, single submitter clinical testing This variant is denoted NF1 c.7907+4_7907+7delAGTA or IVS53+4_IVS53+7delAGTA and consists of a deletion of four nucleotides at the +4 position of intron 53 of the NF1 gene. The surrounding sequence is Tgta[delagta]tctc, where the capital letters are exonic and the lowercase are intronic. In silico models predict that this variant causes abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant, also known as NF1 c.7970+1_+4delGTAA using alternate nomenclature, was observed in an individual with neurofibromatosis type 1 (Maruoka 2014). NF1 c.7907+4_7907+7delAGTA was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The adenine (A) nucleotide that is altered is conserved through mammals. Based on currently available information, it is unclear whether NF1 c.7907+4_7907+7delAGTA is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001225214 SCV001397455 likely pathogenic Neurofibromatosis, type 1 2023-11-02 criteria provided, single submitter clinical testing This sequence change falls in intron 53 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with neurofibromatosis, type 1 (PMID: 25325900; Invitae). This variant is also known as c.7970+1_7970+4delGTAA. ClinVar contains an entry for this variant (Variation ID: 420082). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome-Nilou Lab RCV001225214 SCV002561164 uncertain significance Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Medical Genetics, University of Parma RCV001225214 SCV002567798 likely pathogenic Neurofibromatosis, type 1 2022-08-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV003168948 SCV003897679 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-04-28 criteria provided, single submitter clinical testing The c.7907+4_7907+7delAGTA intronic variant, located in intron 53 of the NF1 gene, results from a deletion of 4 nucleotides within intron 53 of the NF1 gene. This alteration has been reported in an individual with a clinical diagnosis of neurofibromatosis type 1 (Maruoka R et al. Genet Test Mol Biomarkers, 2014 Nov;18:722-35). This alteration is also known as c.7970+1_7970+4delGTAA in the literature. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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