chr17-31229146-T-G
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001042492.3(NF1):c.2531T>G(p.Leu844Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L844F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.2531T>G | p.Leu844Arg | missense_variant | 21/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.2531T>G | p.Leu844Arg | missense_variant | 21/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.2531T>G | p.Leu844Arg | missense_variant | 21/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250420Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135404
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459562Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726088
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 30, 2005 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu844 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10980545, 15060124, 27322474). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt NF1 protein function. ClinVar contains an entry for this variant (Variation ID: 373). This missense change has been observed in individual(s) with neurofibromatosis, type 1 (PMID: 15948193, 29290338). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs137854566, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 844 of the NF1 protein (p.Leu844Arg). - |
Pathogenic, criteria provided, single submitter | clinical testing | Medical Genomics Laboratory, Department of Genetics UAB | Jun 05, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at