12-42459256-GT-G

Variant names:

• chr12-42459256-GT-G
• rs68074167
• NM_153026.3:c.*552delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_153026.3(PRICKLE1):​c.*552delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (48078 hom., cov: 0)
  • Exomes 𝑓: 0.69 (89322 hom.)
• Consequence: PRICKLE1 NM_153026.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.08

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]

PPHLN1 (HGNC:19369): (periphilin 1) The protein encoded by this gene is one of the several proteins that become sequentially incorporated into the cornified cell envelope during the terminal differentiation of keratinocyte at the outer layers of epidermis. This protein interacts with periplakin, which is known as a precursor of the cornified cell envelope. The cellular localization pattern and insolubility of this protein suggest that it may play a role in epithelial differentiation and contribute to epidermal integrity and barrier formation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

ENSG00000257225 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.*552delA		3_prime_UTR_variant	Exon 8 of 8	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127	c.*552delA		3_prime_UTR_variant	Exon 8 of 8	1	NM_153026.3	ENSP00000345064.3

Frequencies

GnomAD3 genomes AF: 0.804 AC: 119254 AN: 148416 Hom.: 48040 Cov.: 0

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.917

Gnomad AMR AF: 0.779

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.828

Gnomad NFE AF: 0.852

Gnomad OTH AF: 0.783

GnomAD2 exomes AF: 0.679 AC: 65772 AN: 96874 AF XY: 0.680

Gnomad AFR exome AF: 0.633

Gnomad AMR exome AF: 0.644

Gnomad ASJ exome AF: 0.663

Gnomad EAS exome AF: 0.675

Gnomad FIN exome AF: 0.717

Gnomad NFE exome AF: 0.706

Gnomad OTH exome AF: 0.666

GnomAD4 exome AF: 0.689 AC: 303638 AN: 440976 Hom.: 89322 Cov.: 0 AF XY: 0.688 AC XY: 164676 AN XY: 239342

African (AFR) AF: 0.613 AC: 7767 AN: 12672

American (AMR) AF: 0.631 AC: 16625 AN: 26330

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 10643 AN: 16092

East Asian (EAS) AF: 0.675 AC: 18108 AN: 26824

South Asian (SAS) AF: 0.655 AC: 32833 AN: 50154

European-Finnish (FIN) AF: 0.727 AC: 19131 AN: 26298

Middle Eastern (MID) AF: 0.753 AC: 2624 AN: 3486

European-Non Finnish (NFE) AF: 0.704 AC: 178977 AN: 254374

Other (OTH) AF: 0.684 AC: 16930 AN: 24746

GnomAD4 genome AF: 0.804 AC: 119350 AN: 148524 Hom.: 48078 Cov.: 0 AF XY: 0.805 AC XY: 58190 AN XY: 72258

African (AFR) AF: 0.721 AC: 29256 AN: 40570

American (AMR) AF: 0.779 AC: 11613 AN: 14904

Ashkenazi Jewish (ASJ) AF: 0.792 AC: 2723 AN: 3436

East Asian (EAS) AF: 0.804 AC: 4106 AN: 5104

South Asian (SAS) AF: 0.782 AC: 3634 AN: 4650

European-Finnish (FIN) AF: 0.862 AC: 8335 AN: 9670

Middle Eastern (MID) AF: 0.818 AC: 239 AN: 292

European-Non Finnish (NFE) AF: 0.852 AC: 57011 AN: 66942

Other (OTH) AF: 0.781 AC: 1602 AN: 2050

Alfa AF: 0.722 Hom.: 4045

Asia WGS AF: 0.735 AC: 2557 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, progressive myoclonic, 1B Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs68074167; hg19: chr12-42853058; COSMIC: COSV58203508; COSMIC: COSV58203508;