chr14-31826715-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate
The NM_025152.3(NUBPL):c.693+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,132 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 Likely pathogenic (★).
Frequency
Consequence
NM_025152.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NUBPL | NM_025152.3 | c.693+1G>A | splice_donor_variant | ENST00000281081.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NUBPL | ENST00000281081.12 | c.693+1G>A | splice_donor_variant | 1 | NM_025152.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249240Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135218
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1460954Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23AN XY: 726848
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
Mitochondrial complex 1 deficiency, nuclear type 21 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 23, 2013 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2023 | Disruption of this splice site has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 29417091, 31917109, 32518176). This variant is present in population databases (rs751631278, gnomAD 0.003%). This sequence change affects a donor splice site in intron 8 of the NUBPL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NUBPL are known to be pathogenic (PMID: 23553477, 31917109). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 50216). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at