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

dbSNP: rs1064794279

Total submissions: 5

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.
Invitae	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	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-11-22	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; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.