rs767805288
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The ENST00000358273.9(NF1):c.3314+1G>A variant causes a splice donor 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 29)
Exomes 𝑓: 7.1e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NF1
ENST00000358273.9 splice_donor
ENST00000358273.9 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.46
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 Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013615023 fraction of the gene. Cryptic splice site detected, with MaxEntScore 2.3, offset of -40, new splice context is: atgGTgtgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-31232190-G-A is Pathogenic according to our data. Variant chr17-31232190-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 573917.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-31232190-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.3314+1G>A | splice_donor_variant | ENST00000358273.9 | NP_001035957.1 | |||
NF1 | NM_000267.3 | c.3314+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.3314+1G>A | splice_donor_variant | 1 | NM_001042492.3 | ENSP00000351015 | P1 |
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD3 genomes
Cov.:
29
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251124Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135732
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.06e-7 AC: 1AN: 1416818Hom.: 0 Cov.: 25 AF XY: 0.00000141 AC XY: 1AN XY: 707398
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome Cov.: 29
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29
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 15, 2022 | 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: 573917). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 23913538, 31443423). This variant is present in population databases (rs767805288, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 25 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at