rs281865563

Variant names:

• chr12-42468783-C-A
• NM_153026.3:c.431G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-42468783-C-A
• chr12-42468783-C-G
• chr12-42468783-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_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. R144H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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 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 rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.431G>T	p.Arg144Leu	missense_variant	Exon 5 of 8	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.431G>T	p.Arg144Leu	missense_variant	Exon 5 of 8	1	NM_153026.3	ENSP00000345064.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727244

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, progressive myoclonic, 1B Uncertain:1

May 15, 2024

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 leucine, which is neutral and non-polar, at codon 144 of the PRICKLE1 protein (p.Arg144Leu). This variant is not present in population databases (gnomAD no frequency). 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: 1475265). 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) performed at Invitae indicates that this missense variant is expected to disrupt PRICKLE1 protein function with a positive predictive value of 80%. 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	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	30
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	D
LIST_S2	Pathogenic	0.98	.;.;.;.;.;.;.;.;.;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;H;H;H;H;H;.
PrimateAI	Uncertain	0.72	T
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	D
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.

Other links and lift over

hg19: chr12-42862585;