chr12-42459718-A-G

Variant names:

• chr12-42459718-A-G
• rs1043652
• ENST00000547824.1:n.353A>G

Variant summary

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

The ENST00000547824.1(ENSG00000257225):​n.353A>G variant causes a non coding transcript exon 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.67 (34650 hom., cov: 33)
  • Exomes 𝑓: 0.64 (273475 hom.)
• Consequence: ENSG00000257225 ENST00000547824.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.407
• Publications: 16 publications found

Genes affected

ENSG00000257225 (HGNC:58444):

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• 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 rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.*91T>C		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.*91T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_153026.3	ENSP00000345064.3

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

African (AFR) AF: 0.755 AC: 22943 AN: 30388

American (AMR) AF: 0.604 AC: 26168 AN: 43300

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 15425 AN: 24944

East Asian (EAS) AF: 0.707 AC: 27611 AN: 39070

South Asian (SAS) AF: 0.747 AC: 61031 AN: 81742

European-Finnish (FIN) AF: 0.608 AC: 32202 AN: 52964

Middle Eastern (MID) AF: 0.632 AC: 2734 AN: 4324

European-Non Finnish (NFE) AF: 0.628 AC: 624408 AN: 993780

Other (OTH) AF: 0.650 AC: 36182 AN: 55634

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

African (AFR) AF: 0.759 AC: 31547 AN: 41540

American (AMR) AF: 0.658 AC: 10053 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2176 AN: 3468

East Asian (EAS) AF: 0.732 AC: 3782 AN: 5170

South Asian (SAS) AF: 0.751 AC: 3621 AN: 4824

European-Finnish (FIN) AF: 0.616 AC: 6510 AN: 10566

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.620 AC: 42144 AN: 67982

Other (OTH) AF: 0.679 AC: 1436 AN: 2114

Alfa AF: 0.640 Hom.: 15028

Bravo AF: 0.673

Asia WGS AF: 0.743 AC: 2580 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Benign	0.79
PhyloP100		0.41
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: rs1043652; hg19: chr12-42853520; COSMIC: COSV58207986; COSMIC: COSV58207986;