17-31227215-T-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_001042492.3(NF1):c.2252-3T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001042492.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.2252-3T>G | splice_region_variant, intron_variant | Intron 18 of 57 | ENST00000358273.9 | NP_001035957.1 | ||
NF1 | NM_000267.3 | c.2252-3T>G | splice_region_variant, intron_variant | Intron 18 of 56 | NP_000258.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:3
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This variant was classified as: Likely pathogenic. -
This sequence change falls in intron 18 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 18546366, 32126153; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 374022). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 19 (also known as exon 14) and introduces a premature termination codon (PMID: 18546366, 32126153). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Neurofibroma;C0221263:Cafe-au-lait spot;C1834297:Inguinal freckling;C1860335:Axillary freckling;C1861975:Cafe au lait spots, multiple Pathogenic:1
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Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
The c.2252-3T>G intronic variant results from a T to G substitution 3 nucleotides upstream from coding exon 19 in the NF1 gene. This variant was detected in individuals with clinical and suspected diagnosis of neurofibromatosis type 1 and reported to result in skipping of exon 19 (Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Wimmer K et al. Hum. Mutat., 2020 Mar; [Epub ahead of print]). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at