17-31227539-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM5PP2BS2_Supporting
The NM_001042492.3(NF1):c.2342A>T(p.His781Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H781P) has been classified as 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.2342A>T | p.His781Leu | missense_variant | 20/58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.3 | c.2342A>T | p.His781Leu | missense_variant | 20/57 | NP_000258.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.2342A>T | p.His781Leu | missense_variant | 20/58 | 1 | NM_001042492.3 | ENSP00000351015.4 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461510Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727062
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 07, 2023 | This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 781 of the NF1 protein (p.His781Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 216398). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF1 protein function with a negative predictive value of 95%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 26, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed as a germline variant in an adult patient with AML; however, no further clinical information was provided (PMID: 34482403); This variant is associated with the following publications: (PMID: 25486365, 34482403) - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 25, 2020 | The c.2342A>T (p.H781L) alteration is located in exon 20 (coding exon 20) of the NF1 gene. This alteration results from a A to T substitution at nucleotide position 2342, causing the histidine (H) at amino acid position 781 to be replaced by a leucine (L). 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 | Jul 16, 2015 | The p.H781L variant (also known as c.2342A>T), located in coding exon 20 of the NF1 gene, results from an A to T substitution at nucleotide position 2342. The histidine at codon 781 is replaced by leucine, an amino acid with similar properties. A similar alteration at the same codon, p.H781P, has been reported in a patient with neurofibromatosis type 1 (NF1) (Fahsold R et al. Am J Hum Genet. 2000 Mar;66(3):790-818).The p.H781Lvariant 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 0.002% (greater than 55000alleles 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.Since supporting evidence is limited at this time, the clinical significance of p.H781Lremains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at