rs4768412

Variant names:

• chr12-42475338-C-T
• rs4768412
• NM_153026.3:c.-48-2774G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153026.3(PRICKLE1):​c.-48-2774G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 152,112 control chromosomes in the GnomAD database, including 8,314 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (8314 hom., cov: 33)
• Consequence: PRICKLE1 NM_153026.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.54
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• epilepsy, progressive myoclonic, 1B

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Unverricht-Lundborg syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• progressive myoclonus epilepsy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.-48-2774G>A		intron_variant	Intron 1 of 7	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.-48-2774G>A		intron_variant	Intron 1 of 7	1	NM_153026.3	ENSP00000345064.3

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48557 AN: 151994 Hom.: 8312 Cov.: 33

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.315

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.319 AC: 48579 AN: 152112 Hom.: 8314 Cov.: 33 AF XY: 0.318 AC XY: 23667 AN XY: 74356

African (AFR) AF: 0.211 AC: 8736 AN: 41488

American (AMR) AF: 0.352 AC: 5376 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1288 AN: 3470

East Asian (EAS) AF: 0.205 AC: 1064 AN: 5182

South Asian (SAS) AF: 0.228 AC: 1100 AN: 4826

European-Finnish (FIN) AF: 0.384 AC: 4053 AN: 10552

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.380 AC: 25845 AN: 67998

Other (OTH) AF: 0.315 AC: 664 AN: 2106

Alfa AF: 0.362 Hom.: 6619

Bravo AF: 0.315

Asia WGS AF: 0.221 AC: 771 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.16
DANN	Benign	0.63
PhyloP100		-3.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4768412; hg19: chr12-42869140;