chr12-42464622-A-G

Position:

• chr12-42464622-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_153026.3(PRICKLE1):​c.1412T>C​(p.Met471Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,892 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: not found (cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.87

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 Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35444844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.1412T>C	p.Met471Thr	missense_variant	7/8	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.1412T>C	p.Met471Thr	missense_variant	7/8	1	NM_153026.3	ENSP00000345064	P1
	ENST00000547824.1	n.1364-79A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251396 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000671

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000529

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2020

The p.M471T variant (also known as c.1412T>C), located in coding exon 6 of the PRICKLE1 gene, results from a T to C substitution at nucleotide position 1412. The methionine at codon 471 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Epilepsy, progressive myoclonic, 1B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 471 of the PRICKLE1 protein (p.Met471Thr). This variant is present in population databases (rs777597253, gnomAD 0.09%). 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: 568656). 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 not expected to disrupt PRICKLE1 protein function with a negative 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	Benign	0.19
BayesDel_addAF	Benign	0.0066	T
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;T;T;T;T;T;T;T;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;.;.;.;.;.;.;.;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.0	L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N;.;N;.;N;.;.;N;.;N
REVEL	Uncertain	0.34
Sift	Benign	0.039	D;.;D;.;D;.;.;D;.;D
Sift4G	Benign	0.67	T;.;T;.;T;.;.;T;.;T
Polyphen		0.70	P;P;P;P;P;P;P;P;P;P
Vest4		0.83
MutPred		0.39		Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);
MVP		0.57
MPC		0.66
ClinPred		0.17	T
GERP RS		5.8
Varity_R		0.52
gMVP		0.34

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: rs777597253; hg19: chr12-42858424;