rs1555617383
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001042492.3(NF1):c.4110+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.4110+1G>A | splice_donor_variant | ENST00000358273.9 | NP_001035957.1 | |||
NF1 | NM_000267.3 | c.4110+1G>A | splice_donor_variant | NP_000258.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.4110+1G>A | splice_donor_variant | 1 | NM_001042492.3 | ENSP00000351015 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251316Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135830
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461642Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727164
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 21, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.4110+1G nucleotide in the NF1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10712197). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 457679). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9003501). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 30 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Cologne University | Dec 29, 2023 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 08, 2022 | PM2_very_strong, PVS1_moderate - |
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 16, 2016 | The c.4110+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 30 of the NF1 gene. This mutation was identified in 1/320 unrelated patients diagnosed with neurofibromatosis type 1 (NF1), and the proband carrying this mutation also had a family history of NF1 (Upadhyaya M et al. Hum. Genet., 1997 Jan;99:88-92). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at