chr8-143927344-T-C

Position:

• chr8-143927344-T-C

Variant summary

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

The NM_201384.3(PLEC):​c.3757-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0263 in 1,612,490 control chromosomes in the GnomAD database, including 8,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (4648 hom., cov: 35)
  • Exomes 𝑓: 0.015 (4166 hom.)
• Consequence: PLEC NM_201384.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001987
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.373

Genes affected

PLEC (HGNC:9069): (plectin) Plectin is a prominent member of an important family of structurally and in part functionally related proteins, termed plakins or cytolinkers, that are capable of interlinking different elements of the cytoskeleton. Plakins, with their multi-domain structure and enormous size, not only play crucial roles in maintaining cell and tissue integrity and orchestrating dynamic changes in cytoarchitecture and cell shape, but also serve as scaffolding platforms for the assembly, positioning, and regulation of signaling complexes (reviewed in PMID: 9701547, 11854008, and 17499243). Plectin is expressed as several protein isoforms in a wide range of cell types and tissues from a single gene located on chromosome 8 in humans (PMID: 8633055, 8698233). Until 2010, this locus was named plectin 1 (symbol PLEC1 in human; Plec1 in mouse and rat) and the gene product had been referred to as "hemidesmosomal protein 1" or "plectin 1, intermediate filament binding 500kDa". These names were superseded by plectin. The plectin gene locus in mouse on chromosome 15 has been analyzed in detail (PMID: 10556294, 14559777), revealing a genomic exon-intron organization with well over 40 exons spanning over 62 kb and an unusual 5' transcript complexity of plectin isoforms. Eleven exons (1-1j) have been identified that alternatively splice directly into a common exon 2 which is the first exon to encode plectin's highly conserved actin binding domain (ABD). Three additional exons (-1, 0a, and 0) splice into an alternative first coding exon (1c), and two additional exons (2alpha and 3alpha) are optionally spliced within the exons encoding the acting binding domain (exons 2-8). Analysis of the human locus has identified eight of the eleven alternative 5' exons found in mouse and rat (PMID: 14672974); exons 1i, 1j and 1h have not been confirmed in human. Furthermore, isoforms lacking the central rod domain encoded by exon 31 have been detected in mouse (PMID:10556294), rat (PMID: 9177781), and human (PMID: 11441066, 10780662, 20052759). The short alternative amino-terminal sequences encoded by the different first exons direct the targeting of the various isoforms to distinct subcellular locations (PMID: 14559777). As the expression of specific plectin isoforms was found to be dependent on cell type (tissue) and stage of development (PMID: 10556294, 12542521, 17389230) it appears that each cell type (tissue) contains a unique set (proportion and composition) of plectin isoforms, as if custom-made for specific requirements of the particular cells. Concordantly, individual isoforms were found to carry out distinct and specific functions (PMID: 14559777, 12542521, 18541706). In 1996, a number of groups reported that patients suffering from epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) lacked plectin expression in skin and muscle tissues due to defects in the plectin gene (PMID: 8698233, 8941634, 8636409, 8894687, 8696340). Two other subtypes of plectin-related EBS have been described: EBS-pyloric atresia (PA) and EBS-Ogna. For reviews of plectin-related diseases see PMID: 15810881, 19945614. Mutations in the plectin gene related to human diseases should be named based on the position in NM_000445 (variant 1, isoform 1c), unless the mutation is located within one of the other alternative first exons, in which case the position in the respective Reference Sequence should be used. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 8-143927344-T-C is Benign according to our data. Variant chr8-143927344-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 93048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143927344-T-C is described in Lovd as [Benign]. Variant chr8-143927344-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLEC	NM_201378.4	c.3715-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000356346.7	NP_958780.1
PLEC	NM_201384.3	c.3757-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000345136.8	NP_958786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8	c.3757-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_201384.3	ENSP00000344848
PLEC	ENST00000356346.7	c.3715-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_201378.4	ENSP00000348702

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20598 AN: 152098 Hom.: 4632 Cov.: 35

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0560

Gnomad ASJ AF: 0.00837

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.0894

GnomAD3 exomes AF: 0.0355 AC: 8622 AN: 243032 Hom.: 1734 AF XY: 0.0273 AC XY: 3617 AN XY: 132580

Gnomad AFR exome AF: 0.480

Gnomad AMR exome AF: 0.0256

Gnomad ASJ exome AF: 0.00812

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.000688

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00250

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0149 AC: 21785 AN: 1460274 Hom.: 4166 Cov.: 35 AF XY: 0.0129 AC XY: 9407 AN XY: 726452

Gnomad4 AFR exome AF: 0.484

Gnomad4 AMR exome AF: 0.0300

Gnomad4 ASJ exome AF: 0.00792

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00109

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.00152

Gnomad4 OTH exome AF: 0.0342

GnomAD4 genome AF: 0.136 AC: 20659 AN: 152216 Hom.: 4648 Cov.: 35 AF XY: 0.131 AC XY: 9734 AN XY: 74452

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.0559

Gnomad4 ASJ AF: 0.00837

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00225

Gnomad4 OTH AF: 0.0889

Alfa AF: 0.0688 Hom.: 885

Bravo AF: 0.155

Asia WGS AF: 0.0340 AC: 119 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 29, 2013	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 18, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Epidermolysis bullosa simplex, Ogna type;C2677349:Epidermolysis bullosa simplex 5C, with pyloric atresia;C2931072:Epidermolysis bullosa simplex 5B, with muscular dystrophy;C3150989:Autosomal recessive limb-girdle muscular dystrophy type 2Q;C4225309:Epidermolysis bullosa simplex with nail dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.9
DANN	Benign	0.15
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.14
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: rs57461687; hg19: chr8-145001512;