NM_001005337.3:c.-130A>T

Variant names:

• chr1-201283573-A-T
• rs861275
• NM_001005337.3:c.-130A>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

PKP1 Gene-Disease associations (from GenCC):

• epidermolysis bullosa simplex due to plakophilin deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005337.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP1	NM_001005337.3	MANE Select	c.-130A>T		5_prime_UTR	Exon 1 of 14	NP_001005337.1	Q13835-2
	PKP1	NM_000299.4		c.-130A>T		5_prime_UTR	Exon 1 of 15	NP_000290.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKP1	ENST00000367324.8	TSL:1 MANE Select	c.-130A>T		5_prime_UTR	Exon 1 of 14	ENSP00000356293.4	Q13835-2
	PKP1	ENST00000263946.7	TSL:5	c.-130A>T		5_prime_UTR	Exon 1 of 15	ENSP00000263946.3	Q13835-1
	PKP1	ENST00000352845.3	TSL:5	c.-130A>T		upstream_gene	N/A	ENSP00000295597.3	Q13835-1

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

African (AFR) AF: 0.186 AC: 3294 AN: 17708

American (AMR) AF: 0.785 AC: 27091 AN: 34490

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 13383 AN: 20438

East Asian (EAS) AF: 0.921 AC: 29865 AN: 32414

South Asian (SAS) AF: 0.746 AC: 47534 AN: 63688

European-Finnish (FIN) AF: 0.735 AC: 26652 AN: 36246

Middle Eastern (MID) AF: 0.687 AC: 1846 AN: 2688

European-Non Finnish (NFE) AF: 0.791 AC: 345536 AN: 436782

Other (OTH) AF: 0.722 AC: 24772 AN: 34298

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

African (AFR) AF: 0.193 AC: 8021 AN: 41484

American (AMR) AF: 0.728 AC: 11144 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.638 AC: 2210 AN: 3464

East Asian (EAS) AF: 0.919 AC: 4733 AN: 5150

South Asian (SAS) AF: 0.749 AC: 3616 AN: 4826

European-Finnish (FIN) AF: 0.723 AC: 7655 AN: 10592

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 53085 AN: 67962

Other (OTH) AF: 0.650 AC: 1371 AN: 2110

Alfa AF: 0.567 Hom.: 2060

Bravo AF: 0.595

Asia WGS AF: 0.760 AC: 2643 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epidermolysis bullosa simplex due to plakophilin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.3
DANN	Benign	0.89
PhyloP100		-0.50
PromoterAI		0.12	Neutral
Mutation Taster		=300/0	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: rs861275; hg19: chr1-201252701;