rs17885739
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The ENST00000358273.9(NF1):c.1845+13A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,608,344 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0095 ( 24 hom., cov: 32)
Exomes 𝑓: 0.0010 ( 24 hom. )
Consequence
NF1
ENST00000358273.9 intron
ENST00000358273.9 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.278
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 17-31223580-A-T is Benign according to our data. Variant chr17-31223580-A-T is described in ClinVar as [Benign]. Clinvar id is 226850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31223580-A-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00947 (1442/152316) while in subpopulation AFR AF= 0.0327 (1358/41544). AF 95% confidence interval is 0.0312. There are 24 homozygotes in gnomad4. There are 690 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1442 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1845+13A>T | intron_variant | ENST00000358273.9 | NP_001035957.1 | |||
NF1 | NM_000267.3 | c.1845+13A>T | intron_variant | NP_000258.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NF1 | ENST00000358273.9 | c.1845+13A>T | intron_variant | 1 | NM_001042492.3 | ENSP00000351015 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00945 AC: 1438AN: 152198Hom.: 24 Cov.: 32
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GnomAD3 exomes AF: 0.00226 AC: 564AN: 249728Hom.: 9 AF XY: 0.00159 AC XY: 216AN XY: 135486
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GnomAD4 exome AF: 0.00102 AC: 1486AN: 1456028Hom.: 24 Cov.: 29 AF XY: 0.000864 AC XY: 626AN XY: 724628
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GnomAD4 genome AF: 0.00947 AC: 1442AN: 152316Hom.: 24 Cov.: 32 AF XY: 0.00926 AC XY: 690AN XY: 74484
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ClinVar
Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 24, 2014 | 1845+13A>T in intron 16 of NF1: This variant is not expected to have clinical si gnificance because it is not located within the conserved splice consensus seque nce. It has been identified in 3.0% (131/4384) of African American chromosomes f rom a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wash ington.edu/EVS; dbSNP rs17885739). - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 16, 2020 | Variant summary: NF1 c.1845+13A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 249728 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1845+13A>T in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Neurofibromatosis, type 1 Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Mar 15, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Neurofibromatosis, familial spinal Benign:1
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at