rs34837068

chr12-42469460-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V125M) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0075 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (185 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.37

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]

ACMG classification

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/exons	MANE	UniProt
PRICKLE1	NM_153026.3	c.374T>C	p.Val125Ala	missense_variant	4/8	ENST00000345127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.374T>C	p.Val125Ala	missense_variant	4/8	1	NM_153026.3	P1

Frequencies

GnomAD3 genomes AF: 0.00750 AC: 1141 AN: 152116 Hom.: 39 Cov.: 32

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

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.: 32 AF XY: 0.00329 AC XY: 2395 AN XY: 727222

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.: 40 Cov.: 32 AF XY: 0.00775 AC XY: 577 AN XY: 74422

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.: 42

Bravo AF: 0.00893

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.000349 AC: 3

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 28, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 06, 2016	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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

PRICKLE1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2019

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	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
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	D
MetaRNN	Benign	0.0040	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.45	N;N;N;N;N;N;N;N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.35	T
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	T
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

Other links and lift over

dbSNP: rs34837068; hg19: chr12-42863262;