rs1555618994
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000358273.9(NF1):c.4578-19A>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 Pathogenic (★★). There are indicators that this mutation may affect the branch point..
Frequency
Genomes: not found (cov: 32)
Consequence
NF1
ENST00000358273.9 intron
ENST00000358273.9 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.57
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.4578-19A>G | intron_variant | ENST00000358273.9 | NP_001035957.1 | |||
NF1 | NM_000267.3 | c.4515-19A>G | intron_variant | NP_000258.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.4578-19A>G | intron_variant | 1 | NM_001042492.3 | ENSP00000351015 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | UAB Medical Genomics Laboratory, UAB Medicine | Jan 20, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 24, 2023 | This sequence change falls in intron 33 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: 32126153; Invitae). ClinVar contains an entry for this variant (Variation ID: 527490). Studies have shown that this variant results in use of a novel splice site and introduces a premature termination codon (PMID: 32126153). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 05, 2024 | Non-canonical splice site variant demonstrated to result in loss of function (PMID: 32126153); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32126153) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
La Branchor
BranchPoint Hunter
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
DS_AL_spliceai
Position offset: 19
Find out detailed SpliceAI scores and Pangolin per-transcript scores at