rs758691069
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM5PP2BP4_ModerateBS2_Supporting
The NM_001042492.3(NF1):c.2032C>A(p.Pro678Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P678A) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.2032C>A | p.Pro678Thr | missense_variant | 18/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.2032C>A | p.Pro678Thr | missense_variant | 18/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.2032C>A | p.Pro678Thr | missense_variant | 18/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250606Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135426
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461532Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12AN XY: 727078
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74282
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | - - |
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 | Nov 09, 2020 | The c.2032C>A (p.P678T) alteration is located in exon 18 (coding exon 18) of the NF1 gene. This alteration results from a C to A substitution at nucleotide position 2032, causing the proline (P) at amino acid position 678 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 23, 2015 | The p.P678T variant (also known as c.2032C>A), located in coding exon 18 of the NF1 gene, results from a C to A substitution at nucleotide position 2032. The proline at codon 678 is replaced by threonine, 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 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 55000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.P678T remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at