rs367986084
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001385284.1(KIT):c.757-6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,612,160 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 Uncertain significance (★★).
Frequency
Consequence
NM_001385284.1 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249790Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135372
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1460034Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 726404
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74322
ClinVar
Submissions by phenotype
not provided Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -
The KIT c.757-9A>G variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs367986084) and ClinVar (classified as a VUS by Invitae for gastrointestinal stomal tumor). The variant was identified in control databases in 6 of 281172 chromosomes at a frequency of 0.00002134 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 1 of 7154 chromosomes (freq: 0.00014) and European (non-Finnish) in 5 of 128344 chromosomes (freq: 0.000039), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The c.575-9A>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However this splicing prediction has not been confirmed by RNA analysis. 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. -
Gastrointestinal stromal tumor Uncertain:1
This sequence change falls in intron 4 of the KIT gene. It does not directly change the encoded amino acid sequence of the KIT protein. This variant is present in population databases (rs367986084, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with KIT-related conditions. ClinVar contains an entry for this variant (Variation ID: 458969). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at