rs34837068

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_153026.3(PRICKLE1):c.374T>C(p.Val125Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,614,068 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 40 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 185 hom. )

Consequence

PRICKLE1
NM_153026.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.37

Variant links:

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]

PRICKLE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039996505).

BP6

Variant 12-42469460-A-G is Benign according to our data. Variant chr12-42469460-A-G is described in ClinVar as [Benign]. Clinvar id is 130028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-42469460-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3 link	c.374T>C	p.Val125Ala	missense_variant	Exon 4 of 8	ENST00000345127.9	NP_694571.2	Q96MT3A0A024R0W7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9 link	c.374T>C	p.Val125Ala	missense_variant	Exon 4 of 8	1	NM_153026.3	ENSP00000345064.3		Q96MT3

Frequencies

GnomAD3 genomes

AF:

0.00750

AC:

1141

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00790

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.0112

AC:

2817

AN:

251386

Hom.:

119

AF XY:

0.00965

AC XY:

1311

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00763

Gnomad AMR exome

AF:

0.0176

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.104

Gnomad SAS exome

AF:

0.00379

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.00652

GnomAD4 exome

AF:

0.00349

AC:

5102

AN:

1461834

Hom.:

185

Cov.:

AF XY:

0.00329

AC XY:

2395

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00756

Gnomad4 AMR exome

AF:

0.0176

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0752

Gnomad4 SAS exome

AF:

0.00376

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000173

Gnomad4 OTH exome

AF:

0.00887

GnomAD4 genome

AF:

0.00750

AC:

1141

AN:

152234

Hom.:

Cov.:

AF XY:

0.00775

AC XY:

577

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00790

Gnomad4 AMR

AF:

0.0122

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.106

Gnomad4 SAS

AF:

0.0106

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00397

Hom.:

Bravo

AF:

0.00893

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0103

AC:

1245

Asia WGS

AF:

0.0420

AC:

144

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 08, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 28, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jan 24, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Epilepsy, progressive myoclonic, 1B

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

PRICKLE1-related disorder

Benign:1

May 29, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T;T;T;T;T;T;T;T;T;T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.42

.;.;.;.;.;.;.;.;.;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.45

N;N;N;N;N;N;N;N;N;N;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.0

N;.;N;.;N;.;.;N;.;N;N;.

REVEL

Benign

0.048

Sift

Benign

0.33

T;.;T;.;T;.;.;T;.;T;T;.

Sift4G

Benign

0.12

T;.;T;.;T;.;.;T;.;T;.;.

Polyphen

0.0010

B;B;B;B;B;B;B;B;B;B;.;.

Vest4

0.25

MPC

0.42

ClinPred

0.0099

GERP RS

4.3

Varity_R

0.046

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over