rs863224655
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001042492.3(NF1):c.1642-449A>G variant causes a 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. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
NF1
NM_001042492.3 intron
NM_001042492.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.791
Genes affected
NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 17-31221401-A-G is Pathogenic according to our data. Variant chr17-31221401-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31221401-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1642-449A>G | intron_variant | ENST00000358273.9 | |||
NF1 | NM_000267.3 | c.1642-449A>G | intron_variant | ||||
NF1 | NM_001128147.3 | c.1642-449A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.1642-449A>G | intron_variant | 1 | NM_001042492.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2022 | NF1: PM2, PP4:Moderate, PS4:Moderate, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 17, 2023 | Published functional studies demonstrate a damaging effect: aberrant splicing, leading to an insertion and frameshift effect (Douben et al., 2022; Koczkowska et al., 2023); In silico analysis supports a deleterious effect on splicing; No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 16479075, 23668869, 36251260, 37186028) - |
Neurofibromatosis, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2021 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in activation of a cryptic splice site, leading to altered splicing and introduction of a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 216394). This variant has been observed in individuals with neurofibromatosis type 1 (PMID: 16479075, 23668869; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 14 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. - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 2023 | The c.1642-449A>G intronic variant results from an A to G substitution 449 nucleotides upstream from coding exon 15 in the NF1 gene. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with neurofibromatosis type 1 (NF1)(Ambry internal data). This variant has been detected in individuals meeting diagnostic criteria for NF1 and RNA studies reported to result in aberrant splicing (Jeong SY et al. J Korean Med Sci, 2006 Feb;21:107-12; Ko JM et al. Pediatr Neurol, 2013 Jun;48:447-53; Douben HCW et al. Hum Mutat, 2022 Dec;43:2130-2140; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at