Variant rs281865563 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_153026.3(PRICKLE1):c.431G>T(p.Arg144Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R144C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PRICKLE1
NM_153026.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-42468783-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE1	NM_153026.3 linkuse as main transcript	c.431G>T	p.Arg144Leu	missense_variant	5/8	ENST00000345127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE1	ENST00000345127.9 linkuse as main transcript	c.431G>T	p.Arg144Leu	missense_variant	5/8	1	NM_153026.3	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Epilepsy, progressive myoclonic, 1B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 28, 2021

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with PRICKLE1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 144 of the PRICKLE1 protein (p.Arg144Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. 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

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;D;D;D;D;D;D;D;D;D;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

4.0

H;H;H;H;H;H;H;H;H;H;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.7

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

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.98

MutPred

0.78

Loss of methylation at R144 (P = 0.0325);Loss of methylation at R144 (P = 0.0325);Loss of methylation at R144 (P = 0.0325);Loss of methylation at R144 (P = 0.0325);Loss of methylation at R144 (P = 0.0325);Loss of methylation at R144 (P = 0.0325);Loss of methylation at R144 (P = 0.0325);Loss of methylation at R144 (P = 0.0325);Loss of methylation at R144 (P = 0.0325);Loss of methylation at R144 (P = 0.0325);Loss of methylation at R144 (P = 0.0325);

MVP

0.96

MPC

1.3

ClinPred

1.0

GERP RS

5.6

Varity_R

0.75

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over