rs757911190
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_153026.3(PRICKLE1):c.1004G>A(p.Arg335Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,595,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
PRICKLE1
NM_153026.3 missense
NM_153026.3 missense
Scores
1
5
12
Clinical Significance
Conservation
PhyloP100: 5.05
Genes affected
PRICKLE1 (HGNC:17019): (prickle planar cell polarity protein 1) This gene encodes a nuclear receptor that may be a negative regulator of the Wnt/beta-catenin signaling pathway. The encoded protein localizes to the nuclear membrane and has been implicated in the nuclear trafficking of the transcription repressors REST/NRSF and REST4. Mutations in this gene have been linked to progressive myoclonus epilepsy. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 3. [provided by RefSeq, Sep 2009]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2152844).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRICKLE1 | NM_153026.3 | c.1004G>A | p.Arg335Gln | missense_variant | 7/8 | ENST00000345127.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRICKLE1 | ENST00000345127.9 | c.1004G>A | p.Arg335Gln | missense_variant | 7/8 | 1 | NM_153026.3 | P1 | |
ENST00000547824.1 | n.1693C>T | non_coding_transcript_exon_variant | 2/2 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152178Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
7
AN:
152178
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000171 AC: 4AN: 233316Hom.: 0 AF XY: 0.0000318 AC XY: 4AN XY: 125858
GnomAD3 exomes
AF:
AC:
4
AN:
233316
Hom.:
AF XY:
AC XY:
4
AN XY:
125858
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000118 AC: 17AN: 1443542Hom.: 0 Cov.: 31 AF XY: 0.0000153 AC XY: 11AN XY: 716702
GnomAD4 exome
AF:
AC:
17
AN:
1443542
Hom.:
Cov.:
31
AF XY:
AC XY:
11
AN XY:
716702
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74334
GnomAD4 genome
?
AF:
AC:
7
AN:
152178
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74334
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
?
AF:
AC:
5
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2021 | The c.1004G>A (p.R335Q) alteration is located in exon 7 (coding exon 6) of the PRICKLE1 gene. This alteration results from a G to A substitution at nucleotide position 1004, causing the arginine (R) at amino acid position 335 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Epilepsy, progressive myoclonic, 1B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 11, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 335 of the PRICKLE1 protein (p.Arg335Gln). This variant is present in population databases (rs757911190, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PRICKLE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 469501). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T;T;T;T;T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M;M;M;M;M;M;M
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;.;N;.;.;N;.;N
REVEL
Benign
Sift
Benign
T;.;T;.;T;.;.;T;.;T
Sift4G
Benign
T;.;T;.;T;.;.;T;.;T
Polyphen
D;D;D;D;D;D;D;D;D;D
Vest4
MutPred
Gain of methylation at K338 (P = 0.0845);Gain of methylation at K338 (P = 0.0845);Gain of methylation at K338 (P = 0.0845);Gain of methylation at K338 (P = 0.0845);Gain of methylation at K338 (P = 0.0845);Gain of methylation at K338 (P = 0.0845);Gain of methylation at K338 (P = 0.0845);Gain of methylation at K338 (P = 0.0845);Gain of methylation at K338 (P = 0.0845);Gain of methylation at K338 (P = 0.0845);
MVP
MPC
1.0
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at