rs145191978
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP6BS2_Supporting
The NM_001042492.3(NF1):c.1588G>A(p.Val530Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00018 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1588G>A | p.Val530Ile | missense_variant | Exon 14 of 58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.3 | c.1588G>A | p.Val530Ile | missense_variant | Exon 14 of 57 | NP_000258.1 | ||
NF1 | NM_001128147.3 | c.1588G>A | p.Val530Ile | missense_variant | Exon 14 of 15 | NP_001121619.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151994Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000797 AC: 20AN: 251002Hom.: 0 AF XY: 0.0000959 AC XY: 13AN XY: 135620
GnomAD4 exome AF: 0.000194 AC: 284AN: 1461588Hom.: 0 Cov.: 33 AF XY: 0.000194 AC XY: 141AN XY: 727044
GnomAD4 genome AF: 0.0000461 AC: 7AN: 151994Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74218
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:1Benign:1Other:1
The NF1 c.1588G>A (p.Val530Ile) missense change has a maximum subpopulation frequency of 0.015% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-29546083-G-A?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). This variant has been observed in an individual with pheochromocytoma who also harbored a pathogenic variant in SDHB (BP5; PMID: 23407919). To our knowledge, this variant has not been reported in individuals with Neurofibromatosis type 1. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP2, BP5. -
- -
This participant was tested at multiple clinical laboratories with differing classifications. The variant was classified, most recently, as Uncertain on 04-29-2017 by GTR ID 26957.AT51 Variant was also classified as Uncertain significance and reported in October 2015 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
not provided Uncertain:1Benign:1
This variant is associated with the following publications: (PMID: 23407919) -
The NF1 p.V530I variant was identified in an individual with pheochromocytoma who was hypertensive but did not exhibit any Neurofibromatosis type 1 symptoms; the patient also had another variant in the SDHB gene which authors reported to be pathogenic (Sjursen_2013_PMID_23407919). The variant was identified in dbSNP (ID: rs145191978) and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae and St. Jude Children's Research Hospital Clinical Genomics Lab, andas likely benign by GeneDx). The variant was identified in control databases in 21 of 282376 chromosomes at a frequency of 0.00007437 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 19 of 128982 chromosomes (freq: 0.000147), Other in 1 of 7214 chromosomes (freq: 0.000139) and African in 1 of 24882 chromosomes (freq: 0.00004), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.V530 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
- -
Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence -
NF1-related disorder Uncertain:1
The NF1 c.1588G>A variant is predicted to result in the amino acid substitution p.Val530Ile. This variant was identified in an individual with adrenal pheochromocytoma and hypertension, but who had no signs or symptoms of neurofibromatosis. The individual also carried a pathogenic variant in the SDHB gene (Sjursen et al. 2013. PubMed ID: 23407919). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141369/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not specified Benign:1
The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. This variant has been identified in at least one clinically healthy individual. This variant has been seen where an alternate explanation for disease was also identified. -
Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Benign:1
- -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at