17-31258502-G-C
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001042492.3(NF1):c.4332G>C(p.Lys1444Asn) variant causes a missense, splice region 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. 14/25 in silico tools predict a damaging outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1444M) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001042492.3 missense, splice_region
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.4332G>C | p.Lys1444Asn | missense_variant, splice_region_variant | 32/58 | ENST00000358273.9 | |
NF1 | NM_000267.3 | c.4269G>C | p.Lys1423Asn | missense_variant, splice_region_variant | 31/57 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.4332G>C | p.Lys1444Asn | missense_variant, splice_region_variant | 32/58 | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.4269G nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 15146469, 31595648). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 404485). This variant has been observed in individual(s) with neurofibromatosis type 1 (PMID: 18546366, 30530636, 31595648; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 1423 of the NF1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NF1 protein. This variant also falls at the last nucleotide of exon 31, which is part of the consensus splice site for this exon. - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 10, 2021 | The c.4269G>C pathogenic mutation (also known as p.K1423N), located in coding exon 31 of the NF1 gene, results from a G to C substitution at nucleotide position 4269. The amino acid change results in lysine to asparagine at codon 1423, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 31, which makes it likely to have some effect on normal mRNA splicing. This mutation has been detected in multiple individuals with a clinical diagnosis or suspicion of neurofibromatosis type 1 (De Luca A et al. Hum. Mutat., 2003 Feb;21:171-2; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Frayling IM et al. J Med Genet, 2019 04;56:209-219; Koczkowska M et al. Hum Mutat, 2020 01;41:299-315). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in skipping of exon 31 (Pros E et al. Hum Mutat, 2008 Sep;29:E173-93; Koczkowska M et al. Hum Mutat, 2020 01;41:299-315; Ambry internal data). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at