rs781255236

Positions:

• chr12-42472417-C-A
• chr12-42472417-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153026.3(PRICKLE1):​c.100G>T​(p.Ala34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42028537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.100G>T	p.Ala34Ser	missense_variant	2/8	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.100G>T	p.Ala34Ser	missense_variant	2/8	1	NM_153026.3	ENSP00000345064.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;.;.;.;.
Eigen	Benign	-0.0062
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	.;.;.;.;.;.;.;.;.;D;D;D;D;.;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.5	L;L;L;L;L;L;L;L;L;L;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	N;.;N;.;N;.;.;N;.;N;N;.;N;N;.
REVEL	Uncertain	0.29
Sift	Benign	0.10	T;.;T;.;T;.;.;T;.;T;T;.;T;T;.
Sift4G	Uncertain	0.050	T;.;T;.;T;.;.;T;.;T;.;.;T;.;.
Polyphen		0.061	B;B;B;B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.26
MutPred		0.65		Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);Loss of catalytic residue at A34 (P = 0.0246);
MVP		0.65
MPC		0.49
ClinPred		0.88	D
GERP RS		4.3
Varity_R		0.17
gMVP		0.27

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: rs781255236; hg19: chr12-42866219;