rs766213678
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM5PP2BS2_Supporting
The NM_001042492.3(NF1):āc.529A>Gā(p.Ile177Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,459,074 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I177K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.529A>G | p.Ile177Val | missense_variant | 5/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.529A>G | p.Ile177Val | missense_variant | 5/57 | ||
NF1 | NM_001128147.3 | c.529A>G | p.Ile177Val | missense_variant | 5/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.529A>G | p.Ile177Val | missense_variant | 5/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251156Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135812
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1459074Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 725966
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 16, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 29, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25589003) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 08, 2015 | The p.I177V variant (also known as c.529A>G), located in coding exon 5 of the NF1 gene, results from an A to G substitution at nucleotide position 529. The isoleucine at codon 177 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55,000alleles tested) in our clinical cohort.This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.<span style="font-family:arial,sans-serif; font-size:9pt">Since supporting evidence is limited at this time, the clinical significance of p.I177V<span style="font-family:arial,sans-serif; font-size:9pt"> remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 10, 2022 | - - |
Neurofibromatosis, type 1 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 16, 2020 | The c.529A>G (p.I177V) alteration is located in exon 5 (coding exon 5) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 529, causing the isoleucine (I) at amino acid position 177 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at