rs863225443
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate
The NM_133259.4(LRPPRC):c.3900+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000207 in 1,448,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_133259.4 splice_donor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LRPPRC | NM_133259.4 | c.3900+1G>T | splice_donor_variant, intron_variant | Intron 35 of 37 | ENST00000260665.12 | NP_573566.2 | ||
LRPPRC | XM_006711915.3 | c.3822+1G>T | splice_donor_variant, intron_variant | Intron 35 of 37 | XP_006711978.1 | |||
LRPPRC | XM_047442809.1 | c.3774+1G>T | splice_donor_variant, intron_variant | Intron 35 of 37 | XP_047298765.1 | |||
LRPPRC | XR_007068563.1 | n.3942+1G>T | splice_donor_variant, intron_variant | Intron 35 of 37 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251398Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135876
GnomAD4 exome AF: 0.00000207 AC: 3AN: 1448292Hom.: 0 Cov.: 28 AF XY: 0.00000416 AC XY: 3AN XY: 721400
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 35, but is expected to preserve the integrity of the reading-frame (PMID: 26510952). Disruption of this splice site has been observed in individuals with clinical features of Leigh Syndrome (PMID: 26510951). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change affects a donor splice site in intron 35 of the LRPPRC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at