rs386833659
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong
The NM_000310.4(PPT1):c.628-1G>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,612,482 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_000310.4 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PPT1 | NM_000310.4 | c.628-1G>T | splice_acceptor_variant | ENST00000642050.2 | |||
PPT1 | NM_001142604.2 | c.319-1G>T | splice_acceptor_variant | ||||
PPT1 | NM_001363695.2 | c.628-1G>T | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PPT1 | ENST00000642050.2 | c.628-1G>T | splice_acceptor_variant | NM_000310.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460364Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726588
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74330
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 1 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 03, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 21, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 30, 2023 | For these reasons, this variant has been classified as 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: 56208). This variant is also known as IVS6-1G>T. Disruption of this splice site has been observed in individual(s) with infantile neuronal ceroid lipofuscinosis (PMID: 10679943). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 6 of the PPT1 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 PPT1 are known to be pathogenic (PMID: 10679943, 21990111). - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 07, 2016 | - - |
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 06, 2016 | Variant summary: The c.628-1G>T in a PPT1 gene is a splice-site variant that alters a conserved nucleotide. 5/5 in silico tools in Alamut predict this variant to disrupt a canonical acceptor sequence, however these predictions have yet to be confirmed by functional assay. The variant is absent from ExAC but has been reported in multiple affected patients presented with infantile neuronal ceroid lipofuscinoses. In addition, a reputable database/diagnostic center classified the variant of interest as Likely Pathogenic. Taken together, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at