12-42459718-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_153026.3(PRICKLE1):c.*91T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 1,478,296 control chromosomes in the GnomAD database, including 308,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.67 (34650 hom., cov: 33)
  • Exomes 𝑓: 0.64 (273475 hom.)
• Consequence: PRICKLE1 NM_153026.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.407

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:):

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-42459718-A-G is Benign according to our data. Variant chr12-42459718-A-G is described in ClinVar as [Benign]. Clinvar id is 1291049.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE1	NM_153026.3	c.*91T>C		3_prime_UTR_variant	8/8	ENST00000345127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.*91T>C		3_prime_UTR_variant	8/8	1	NM_153026.3	P1
	ENST00000547824.1	n.353A>G		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101919 AN: 152032 Hom.: 34605 Cov.: 33

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.731

Gnomad SAS AF: 0.751

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.677

GnomAD4 exome AF: 0.640 AC: 848704 AN: 1326146 Hom.: 273475 Cov.: 19 AF XY: 0.642 AC XY: 428271 AN XY: 666970

Gnomad4 AFR exome AF: 0.755

Gnomad4 AMR exome AF: 0.604

Gnomad4 ASJ exome AF: 0.618

Gnomad4 EAS exome AF: 0.707

Gnomad4 SAS exome AF: 0.747

Gnomad4 FIN exome AF: 0.608

Gnomad4 NFE exome AF: 0.628

Gnomad4 OTH exome AF: 0.650

GnomAD4 genome AF: 0.671 AC: 102022 AN: 152150 Hom.: 34650 Cov.: 33 AF XY: 0.673 AC XY: 50071 AN XY: 74378

Gnomad4 AFR AF: 0.759

Gnomad4 AMR AF: 0.658

Gnomad4 ASJ AF: 0.627

Gnomad4 EAS AF: 0.732

Gnomad4 SAS AF: 0.751

Gnomad4 FIN AF: 0.616

Gnomad4 NFE AF: 0.620

Gnomad4 OTH AF: 0.679

Alfa AF: 0.636 Hom.: 12382

Bravo AF: 0.673

Asia WGS AF: 0.743 AC: 2580 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	14
Dann	Benign	0.79

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: rs1043652; hg19: chr12-42853520; COSMIC: COSV58207986; COSMIC: COSV58207986;