rs1043656

Variant names:

• chr12-42459548-A-G
• rs1043656
• ENST00000547824.1:n.183A>G

Variant summary

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

The ENST00000547824.1(ENSG00000257225):​n.183A>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 0.335 in 615,396 control chromosomes in the GnomAD database, including 37,198 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 0.30 (7719 hom., cov: 32)
  • Exomes 𝑓: 0.35 (29479 hom.)
• Consequence: ENSG00000257225 ENST00000547824.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.832
• Publications: 14 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.*261T>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.*261T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_153026.3	ENSP00000345064.3

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45092 AN: 151938 Hom.: 7717 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.299

GnomAD4 exome AF: 0.348 AC: 161202 AN: 463340 Hom.: 29479 Cov.: 3 AF XY: 0.344 AC XY: 84639 AN XY: 246128

African (AFR) AF: 0.132 AC: 1679 AN: 12758

American (AMR) AF: 0.371 AC: 7440 AN: 20030

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 5409 AN: 14166

East Asian (EAS) AF: 0.241 AC: 7588 AN: 31492

South Asian (SAS) AF: 0.252 AC: 11771 AN: 46670

European-Finnish (FIN) AF: 0.398 AC: 12153 AN: 30560

Middle Eastern (MID) AF: 0.362 AC: 792 AN: 2186

European-Non Finnish (NFE) AF: 0.378 AC: 105434 AN: 278796

Other (OTH) AF: 0.335 AC: 8936 AN: 26682

GnomAD4 genome AF: 0.297 AC: 45113 AN: 152056 Hom.: 7719 Cov.: 32 AF XY: 0.297 AC XY: 22049 AN XY: 74316

African (AFR) AF: 0.127 AC: 5282 AN: 41514

American (AMR) AF: 0.348 AC: 5317 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1291 AN: 3470

East Asian (EAS) AF: 0.206 AC: 1066 AN: 5172

South Asian (SAS) AF: 0.238 AC: 1147 AN: 4818

European-Finnish (FIN) AF: 0.384 AC: 4048 AN: 10542

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25880 AN: 67950

Other (OTH) AF: 0.299 AC: 630 AN: 2108

Alfa AF: 0.349 Hom.: 12790

Bravo AF: 0.289

Asia WGS AF: 0.219 AC: 767 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	-0.83
CADD	Benign	11
DANN	Benign	0.63
PhyloP100		0.83
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: rs1043656; hg19: chr12-42853350; COSMIC: COSV58211154; COSMIC: COSV58211154;