rs748245325
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_001042492.3(NF1):c.7190-5T>C variant causes a splice region, 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
NF1
NM_001042492.3 splice_region, intron
NM_001042492.3 splice_region, intron
Scores
2
Splicing: ADA: 0.001551
2
Clinical Significance
Conservation
PhyloP100: 0.402
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_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.41).
BP6
Variant 17-31349115-T-C is Benign according to our data. Variant chr17-31349115-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 232454.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.7190-5T>C | splice_region_variant, intron_variant | ENST00000358273.9 | NP_001035957.1 | |||
NF1 | NM_000267.3 | c.7127-5T>C | splice_region_variant, intron_variant | NP_000258.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.7190-5T>C | splice_region_variant, intron_variant | 1 | NM_001042492.3 | ENSP00000351015.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000498 AC: 1AN: 200670Hom.: 0 AF XY: 0.00000931 AC XY: 1AN XY: 107436
GnomAD3 exomes
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1
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200670
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1
AN XY:
107436
Gnomad AFR exome
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GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 20, 2021 | The c.7127-5T>C intronic alteration consists of a T to C substitution 5 nucleotides before coding exon 48 in the NF1 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 19, 2015 | Thec.7190-5T>Cintronicvariant results from a T to C substitution 5 nucleotides upstream from codingexon49 in theNF1gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP),NHLBIExomeSequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than55000 alleles tested) in our clinical cohort.This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfindersplice site prediction tools, this alteration is not predicted to have any significant effect on this acceptor splice site; however, direct evidence is unavailable.Since supporting evidence is limited at this time, the clinical significance of c.7190-5T>Cremains unclear. - |
Neurofibromatosis, type 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at