NM_001042492.3:c.1392G>T
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BS2_Supporting
The NM_001042492.3(NF1):c.1392G>T(p.Pro464Pro) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000958 in 1,461,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P464P) has been classified as Likely benign.
Frequency
Consequence
NM_001042492.3 splice_region, synonymous
Scores
Clinical Significance
Conservation
Publications
- neurofibromatosis type 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
- neurofibromatosis-Noonan syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
- Moyamoya diseaseInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1392G>T | p.Pro464Pro | splice_region_variant, synonymous_variant | Exon 12 of 58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.4 | c.1392G>T | p.Pro464Pro | splice_region_variant, synonymous_variant | Exon 12 of 57 | NP_000258.1 | ||
NF1 | NM_001128147.3 | c.1392G>T | p.Pro464Pro | splice_region_variant, synonymous_variant | Exon 12 of 15 | NP_001121619.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461270Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 726958 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:1
This sequence change affects codon 464 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 404557). 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 is not likely to affect RNA splicing. 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. -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
The c.1392G>T variant (also known as p.P464P), located in coding exon 12 of the NF1 gene, results from a G to T substitution at nucleotide position 1392. This nucleotide substitution does not change the proline at codon 464. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive; 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at