rs142163063
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000391.4(TPP1):c.7C>A(p.Leu3Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000396 in 1,614,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L3L) has been classified as Likely benign.
Frequency
Consequence
NM_000391.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPP1 | NM_000391.4 | c.7C>A | p.Leu3Ile | missense_variant | 1/13 | ENST00000299427.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPP1 | ENST00000299427.12 | c.7C>A | p.Leu3Ile | missense_variant | 1/13 | 1 | NM_000391.4 | P1 | |
ENST00000545572.1 | n.94G>T | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000230 AC: 35AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251492Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135918
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727248
GnomAD4 genome ? AF: 0.000230 AC: 35AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16AN XY: 74486
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 12, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2016 | The L3I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L3I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Autosomal recessive spinocerebellar ataxia 7;C1876161:Neuronal ceroid lipofuscinosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Dec 29, 2022 | This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.08% [13/15282]; https://gnomad.broadinstitute.org/variant/11-6619394-G-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID: 207558). Evolutionary conservation and computational prediction tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 22, 2022 | The c.7C>A (p.L3I) alteration is located in exon 1 (coding exon 1) of the TPP1 gene. This alteration results from a C to A substitution at nucleotide position 7, causing the leucine (L) at amino acid position 3 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Neuronal ceroid lipofuscinosis 2 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at