rs559947948

Positions:

• chr12-42465210-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 10.0

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE1	NM_153026.3	c.824C>T	p.Thr275Met	missense_variant	7/8	ENST00000345127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.824C>T	p.Thr275Met	missense_variant	7/8	1	NM_153026.3	P1
	ENST00000547824.1	n.1873G>A		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152176 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000117 AC: 29 AN: 248256 Hom.: 0 AF XY: 0.000134 AC XY: 18 AN XY: 134362

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 SAS exome AF: 0.00

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.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 726760

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000473

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000164

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74462

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000156 Hom.: 0

Bravo AF: 0.000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, progressive myoclonic, 1B Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Mendelics	Aug 12, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 06, 2021	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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 25, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
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	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.2	M;M;M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
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	D
GERP RS		5.1
Varity_R		0.74
gMVP		0.46

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: rs559947948; hg19: chr12-42859012; COSMIC: COSV100566109; COSMIC: COSV100566109;