1-201283573-A-T

Position:

• chr1-201283573-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001005337.3(PKP1):​c.-130A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.737 in 830,844 control chromosomes in the GnomAD database, including 236,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (33417 hom., cov: 33)
  • Exomes 𝑓: 0.77 (203353 hom.)
• Consequence: PKP1 NM_001005337.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.501

Genes affected

PKP1 (HGNC:9023): (plakophilin 1) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This protein may be involved in molecular recruitment and stabilization during desmosome formation. Mutations in this gene have been associated with the ectodermal dysplasia/skin fragility syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-201283573-A-T is Benign according to our data. Variant chr1-201283573-A-T is described in ClinVar as [Benign]. Clinvar id is 294795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKP1	NM_001005337.3	c.-130A>T		5_prime_UTR_variant	1/14	ENST00000367324.8	NP_001005337.1
PKP1	NM_000299.4	c.-130A>T		5_prime_UTR_variant	1/15		NP_000290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKP1	ENST00000367324.8	c.-130A>T		5_prime_UTR_variant	1/14	1	NM_001005337.3	ENSP00000356293	P1
PKP1	ENST00000263946.7	c.-130A>T		5_prime_UTR_variant	1/15	5		ENSP00000263946

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92660 AN: 151974 Hom.: 33408 Cov.: 33

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.745

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.638

Gnomad EAS AF: 0.919

Gnomad SAS AF: 0.749

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.650

GnomAD4 exome AF: 0.766 AC: 519973 AN: 678752 Hom.: 203353 Cov.: 9 AF XY: 0.767 AC XY: 274080 AN XY: 357480

Gnomad4 AFR exome AF: 0.186

Gnomad4 AMR exome AF: 0.785

Gnomad4 ASJ exome AF: 0.655

Gnomad4 EAS exome AF: 0.921

Gnomad4 SAS exome AF: 0.746

Gnomad4 FIN exome AF: 0.735

Gnomad4 NFE exome AF: 0.791

Gnomad4 OTH exome AF: 0.722

GnomAD4 genome AF: 0.609 AC: 92678 AN: 152092 Hom.: 33417 Cov.: 33 AF XY: 0.612 AC XY: 45509 AN XY: 74342

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.728

Gnomad4 ASJ AF: 0.638

Gnomad4 EAS AF: 0.919

Gnomad4 SAS AF: 0.749

Gnomad4 FIN AF: 0.723

Gnomad4 NFE AF: 0.781

Gnomad4 OTH AF: 0.650

Alfa AF: 0.567 Hom.: 2060

Bravo AF: 0.595

Asia WGS AF: 0.760 AC: 2643 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Epidermolysis bullosa simplex due to plakophilin deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.3
DANN	Benign	0.89

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: rs861275; hg19: chr1-201252701;