rs778232650
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000391.4(TPP1):βc.972_979delβ(p.Ser324ArgfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. S324S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000391.4 frameshift
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 |
---|---|---|---|---|---|---|---|
TPP1 | NM_000391.4 | c.972_979del | p.Ser324ArgfsTer2 | frameshift_variant | 8/13 | ENST00000299427.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.972_979del | p.Ser324ArgfsTer2 | frameshift_variant | 8/13 | 1 | NM_000391.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251378Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135870
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461754Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727186
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 2 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 23, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 20, 2020 | Variant summary: TPP1 c.972_979delCTATGGAG (p.Ser324ArgfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251378 control chromosomes (gnomAD). c.972_979delCTATGGAG has been reported in the literature in individuals affected with Late-infantile Neuronal Ceroid-Lipofuscinoses (Sleat_1999). These data indicate that the variant may be associated with disease. At least one publication reports this variant has an impact on protein function and results in <10% of normal TPP1 activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change creates a premature translational stop signal (p.Ser324Argfs*2) in the TPP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPP1 are known to be pathogenic (PMID: 10330339). This variant is present in population databases (rs778232650, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 10330339). This variant is also known as 4288-4295del. ClinVar contains an entry for this variant (Variation ID: 188850). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at