NM_153026.3:c.1004G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.05

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2152844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3 link	c.1004G>A	p.Arg335Gln	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.1004G>A	p.Arg335Gln	missense_variant	Exon 7 of 8	1	NM_153026.3	ENSP00000345064.3		Q96MT3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000171

AC:

AN:

233316

AF XY:

0.0000318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000279

Gnomad OTH exome

AF:

0.000180

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1443542

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

716702

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32696

American (AMR)

AF:

0.00

AC:

AN:

41556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24898

East Asian (EAS)

AF:

0.00

AC:

AN:

39540

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82958

European-Finnish (FIN)

AF:

0.0000568

AC:

AN:

52858

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

1103948

Other (OTH)

AF:

0.00

AC:

AN:

59432

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000460

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000712

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 03, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jul 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.0057

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.082

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

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.020

MetaRNN

Benign

0.22

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

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.2

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

PhyloP100

5.1

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.55

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

REVEL

Benign

0.16

Sift

Benign

0.070

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

Sift4G

Benign

0.17

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

Polyphen

0.99

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

Vest4

0.27

MutPred

0.24

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

0.68

MPC

1.0

ClinPred

0.36

GERP RS

4.4

Varity_R

0.089

gMVP

0.50

Mutation Taster

=83/17

polymorphism

(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