rs559947948

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 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

Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

PRICKLE1
NM_153026.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 10.0

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

epilepsy, progressive myoclonic, 1B
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Unverricht-Lundborg syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
progressive myoclonus epilepsy
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PRICKLE1 links:

ENSG00000257225 (HGNC:58444):

ENSG00000257225 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3 link	c.824C>T	p.Thr275Met	missense_variant	Exon 7 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.824C>T	p.Thr275Met	missense_variant	Exon 7 of 8	1	NM_153026.3	ENSP00000345064.3		Q96MT3

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000117

AC:

AN:

248256

AF XY:

0.000134

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000380

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000108

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000157

AC:

230

AN:

1460862

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

726760

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33414

American (AMR)

AF:

0.000473

AC:

AN:

44368

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26074

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86056

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000164

AC:

182

AN:

1111734

Other (OTH)

AF:

0.000199

AC:

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41560

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000134

Hom.:

Bravo

AF:

0.000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epilepsy, progressive myoclonic, 1B

Uncertain:3

Aug 12, 2022

Mendelics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Uncertain:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 25, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 25, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2

Aug 10, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 06, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PRICKLE1-related disorder

Uncertain:1

Aug 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PRICKLE1 c.824C>T variant is predicted to result in the amino acid substitution p.Thr275Met. This variant was reported as possibly damaging in an individual with lumbosacral myelomeningocele, hydrocephalus, Chiari type II malformation, and tethered cord (Bosoi et al. 2011. PubMed ID: 21901791). This variant is reported in 0.037% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

D;D;D;D;D;D;D;D;D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;.;.;.;.;.;.;.;.;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Pathogenic

3.2

M;M;M;M;M;M;M;M;M;M

PhyloP100

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.3

D;.;D;.;D;.;.;D;.;D

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

D;.;D;.;D;.;.;D;.;D

Sift4G

Pathogenic

0.0010

D;.;D;.;D;.;.;D;.;D

Polyphen

1.0

D;D;D;D;D;D;D;D;D;D

Vest4

0.94

MutPred

0.43

Gain of catalytic residue at T275 (P = 0.0599);Gain of catalytic residue at T275 (P = 0.0599);Gain of catalytic residue at T275 (P = 0.0599);Gain of catalytic residue at T275 (P = 0.0599);Gain of catalytic residue at T275 (P = 0.0599);Gain of catalytic residue at T275 (P = 0.0599);Gain of catalytic residue at T275 (P = 0.0599);Gain of catalytic residue at T275 (P = 0.0599);Gain of catalytic residue at T275 (P = 0.0599);Gain of catalytic residue at T275 (P = 0.0599);

MVP

0.83

MPC

1.1

ClinPred

0.75

GERP RS

5.1

Varity_R

0.74

gMVP

0.46

Mutation Taster

=6/94

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over