rs199474791
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_001042492.3(NF1):c.5854T>A(p.Trp1952Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1952C) has been classified as Pathogenic.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 06, 2020 | For these reasons, this variant has been classified as Pathogenic. A different variant (c.5791T>C) giving rise to the same protein effect observed here (p.Trp1931Arg) has been determined to be pathogenic (PMID: 9101300, 17311297, 16944272, 23244495, 29914388). This suggests that this variant is also likely to be causative of disease. 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. This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 27838393). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 1931 of the NF1 protein (p.Trp1931Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.