17-31265340-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_001042492.3(NF1):c.4835+1G>T variant causes a splice donor, intron 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. 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, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 26
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. 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: 426827). This variant is also known as c.4835+1G>T. Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 29588991; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 35 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). -
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not provided Pathogenic:1
The c.4772+1 G>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It destroys the canonical splice donor site in intron 35 and leads to abnormal gene splicing; however, the adjacent exon 35 remains in frame. A portion of exon 35 (residues 1555 to 1591) lies within the CRAL-TRIO domain and lipid-binding region. The c.4772+1 G>T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. In summary, we consider this variant to be likely pathogenic. -
Juvenile myelomonocytic leukemia Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at