17-31156014-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_001042492.3(NF1):āc.92A>Gā(p.His31Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H31Y) 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.92A>G | p.His31Arg | missense_variant | 2/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.92A>G | p.His31Arg | missense_variant | 2/57 | ||
NF1 | NM_001128147.3 | c.92A>G | p.His31Arg | missense_variant | 2/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.92A>G | p.His31Arg | missense_variant | 2/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461496Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727050
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | 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. 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: 68364). This missense change has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 15060124). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 31 of the NF1 protein (p.His31Arg). - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 22, 2022 | The p.H31R variant (also known as c.92A>G), located in coding exon 2 of the NF1 gene, results from an A to G substitution at nucleotide position 92. The histidine at codon 31 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in 1/91 probands fulfilling the NIH diagnostic criteria for neurofibromatosis type 1 (NF1) (Mattocks C et al. J. Med. Genet., 2004 Apr;41:e48). Another study that assessed missense mutations by combining protein network data with mutational analyses based on 3D structures using the protein design algorithm FoldX found this alteration to have no effect (Kiel C et al. Mol. Syst. Biol., 2014 May;10:727). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. - |
not provided Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at