chr17-31338008-G-A
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001042492.3(NF1):c.6705-17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
NF1
NM_001042492.3 intron
NM_001042492.3 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.671
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 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-31338008-G-A is Pathogenic according to our data. Variant chr17-31338008-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422739.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=1}.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1443792Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 719514
GnomAD4 exome
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1
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1443792
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29
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0
AN XY:
719514
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neurofibromatosis, type 1 Pathogenic:3Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | UAB Medical Genomics Laboratory, UAB Medicine | Jan 20, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Medical University Innsbruck | Jan 20, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 30, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 32126153). ClinVar contains an entry for this variant (Variation ID: 422739). This variant has been observed in individual(s) with clinical features of neurofibromatosis, type 1 (PMID: 32126153). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 43 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2016 | This variant is denoted NF1 c.6642-17G>A or IVS43-17G>A and consists of a G>A nucleotide substitution at the -17 position of intron 43 of the NF1 gene. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. In silico models are uninformative, and in the absence of RNA or functional studies, the actual effect of this variant is unknown. NF1 c.6642-17G>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The guanine (G) nucleotide that is altered is not conserved across species. Based on currently available information, it is unclear whether NF1 c.6642-17G>A is pathogenic or benign. We consider it to be a variant of uncertain significance. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 17
Find out detailed SpliceAI scores and Pangolin per-transcript scores at