chr12-42465210-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_153026.3(PRICKLE1):c.824C>T(p.Thr275Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,613,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T275T) has been classified as Likely benign.
Frequency
Consequence
NM_153026.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRICKLE1 | NM_153026.3 | c.824C>T | p.Thr275Met | missense_variant | 7/8 | ENST00000345127.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRICKLE1 | ENST00000345127.9 | c.824C>T | p.Thr275Met | missense_variant | 7/8 | 1 | NM_153026.3 | P1 | |
ENST00000547824.1 | n.1873G>A | non_coding_transcript_exon_variant | 2/2 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000117 AC: 29AN: 248256Hom.: 0 AF XY: 0.000134 AC XY: 18AN XY: 134362
GnomAD4 exome AF: 0.000157 AC: 230AN: 1460862Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108AN XY: 726760
GnomAD4 genome AF: 0.0000985 AC: 15AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74462
ClinVar
Submissions by phenotype
Epilepsy, progressive myoclonic, 1B Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Mendelics | Aug 12, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 275 of the PRICKLE1 protein (p.Thr275Met). This variant is present in population databases (rs559947948, gnomAD 0.04%). This missense change has been observed in individual(s) with neural tube defects (PMID: 21901791). ClinVar contains an entry for this variant (Variation ID: 180205). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PRICKLE1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2023 | Variant summary: PRICKLE1 c.824C>T (p.Thr275Met) results in a non-conservative amino acid change located in the LIM3 prickle domain (IPR033727) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 248256 control chromosomes (gnomAD). c.824C>T has been reported in the literature in at least one individual affected with Neural tube defects (Bosoi_2011). This report does not provide unequivocal conclusions about association of the variant with Epilepsy, progressive myoclonic, 1B. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 21901791). Six ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2021 | The c.824C>T (p.T275M) alteration is located in exon 7 (coding exon 6) of the PRICKLE1 gene. This alteration results from a C to T substitution at nucleotide position 824, causing the threonine (T) at amino acid position 275 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 25, 2018 | A variant of uncertain significance has been identified in the PRICKLE1 gene. The T275M variant has been reported previously in an individual with lumbosacral myelomeningocele, hydrocephalus, Chiari type II malformation, and tethered cord (Bosoi et al., 2011). However, this variant has not been reported in association with epilepsy. The T275M variant is observed in 13/34074 (0.04%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The T275M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 25, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at