rs369372561
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_016492.5(RANGRF):c.77+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000404 in 1,614,116 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_016492.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000250 AC: 38AN: 152260Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000268 AC: 67AN: 250336Hom.: 0 AF XY: 0.000243 AC XY: 33AN XY: 135744
GnomAD4 exome AF: 0.000420 AC: 614AN: 1461856Hom.: 1 Cov.: 32 AF XY: 0.000385 AC XY: 280AN XY: 727240
GnomAD4 genome AF: 0.000250 AC: 38AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74396
ClinVar
Submissions by phenotype
Cardiac arrhythmia Uncertain:2
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This sequence change falls in intron 1 of the RANGRF gene. It does not directly change the encoded amino acid sequence of the RANGRF protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs369372561, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RANGRF-related conditions. ClinVar contains an entry for this variant (Variation ID: 392547). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. -
not provided Uncertain:1
Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports a deleterious effect on splicing; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at