rs201604273
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP3BP6BS2_Supporting
The NM_001042492.3(NF1):c.1392G>A(p.Pro464=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000143 in 1,613,452 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P464P) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1392G>A | p.Pro464= | splice_region_variant, synonymous_variant | 12/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.1392G>A | p.Pro464= | splice_region_variant, synonymous_variant | 12/57 | ||
NF1 | NM_001128147.3 | c.1392G>A | p.Pro464= | splice_region_variant, synonymous_variant | 12/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.1392G>A | p.Pro464= | splice_region_variant, synonymous_variant | 12/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152064Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251398Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135864
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461270Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 726958
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74394
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2022 | In silico analysis supports that this variant does not alter splicing; Has not been previously published as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 21520333, 26956871, 29121415, 24296828) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 20, 2015 | The c.1392G>A variant (also known as p.P464P) is located in coding exon 12 of the NF1 gene. This variant results from a G to A substitution at nucleotide position 1392. This nucleotide substitution does not change codon 464. However, this change occurs in the last base pair of exon 12 which makes it likely to have some effect on normal mRNA splicing. This variant was previously reported in the SNPDatabase as rs201604273. Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.56% (1/178) Japanese alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles.<span style="background-color:initial">To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 110000 alleles tested) in our clinical cohort. <span style="background-color:initial">This nucleotide position is not well conserved in available vertebrate species, and A is the frequent alternate allele. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native donor splice site; however, direct evidence is unavailable. <span style="background-color:initial">Since supporting evidence is limited at this time, the clinical significance of<span style="background-color:initial">c.1392G>A<span style="background-color:initial">remains unclear. - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 22, 2021 | This alteration is classified as likely 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at