12-42459256-GTT-GTTT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_153026.3(PRICKLE1):​c.*552dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000094 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0029 (0 hom.)
• Consequence: PRICKLE1 NM_153026.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 3 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]

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:58444):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.*552dupA		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	ENST00000345127.9	c.*552dupA		3_prime_UTR_variant	Exon 8 of 8	1	NM_153026.3	ENSP00000345064.3

Frequencies

GnomAD3 genomes AF: 0.0000943 AC: 14 AN: 148478 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00137

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000448

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00437 AC: 423 AN: 96874 AF XY: 0.00413

Gnomad AFR exome AF: 0.00620

Gnomad AMR exome AF: 0.00725

Gnomad ASJ exome AF: 0.00390

Gnomad EAS exome AF: 0.00568

Gnomad FIN exome AF: 0.00327

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.00291 AC: 1270 AN: 436484 Hom.: 0 Cov.: 0 AF XY: 0.00303 AC XY: 717 AN XY: 236774

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00632 AC: 78 AN: 12348

American (AMR) AF: 0.00605 AC: 157 AN: 25950

Ashkenazi Jewish (ASJ) AF: 0.00447 AC: 71 AN: 15884

East Asian (EAS) AF: 0.00351 AC: 93 AN: 26478

South Asian (SAS) AF: 0.00472 AC: 233 AN: 49402

European-Finnish (FIN) AF: 0.00145 AC: 38 AN: 26146

Middle Eastern (MID) AF: 0.00173 AC: 6 AN: 3466

European-Non Finnish (NFE) AF: 0.00205 AC: 518 AN: 252370

Other (OTH) AF: 0.00311 AC: 76 AN: 24440

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000942 AC: 14 AN: 148586 Hom.: 0 Cov.: 0 AF XY: 0.000124 AC XY: 9 AN XY: 72292

African (AFR) AF: 0.0000493 AC: 2 AN: 40594

American (AMR) AF: 0.000134 AC: 2 AN: 14908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00137 AC: 7 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000448 AC: 3 AN: 66960

Other (OTH) AF: 0.00 AC: 0 AN: 2050

Alfa AF: 0.00442 Hom.: 4045

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs68074167; hg19: chr12-42853058;