rs11991798

chr8-143928005-C-T

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.3261-13G>A 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 0.0177 in 1,587,154 control chromosomes in the GnomAD database, including 3,021 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (1549 hom., cov: 34)
  • Exomes 𝑓: 0.011 (1472 hom.)
• Consequence: PLEC NM_201384.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.172

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 These names were superseded by plectin.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=-0.89).
• BP6: Variant 8-143928005-C-T is Benign according to our data. Variant chr8-143928005-C-T is described in ClinVar as [Benign]. Clinvar id is 93041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143928005-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEC	NM_201378.4	c.3219-13G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000356346.7
PLEC	NM_201384.3	c.3261-13G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000345136.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEC	ENST00000345136.8	c.3261-13G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_201384.3
PLEC	ENST00000356346.7	c.3219-13G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_201378.4

Frequencies

GnomAD3 genomes AF: 0.0794 AC: 12087 AN: 152196 Hom.: 1540 Cov.: 34

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0311

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.0664

GnomAD3 exomes AF: 0.0216 AC: 4995 AN: 231086 Hom.: 554 AF XY: 0.0169 AC XY: 2159 AN XY: 127648

Gnomad AFR exome AF: 0.278

Gnomad AMR exome AF: 0.0142

Gnomad ASJ exome AF: 0.00111

Gnomad EAS exome AF: 0.000170

Gnomad SAS exome AF: 0.000340

Gnomad FIN exome AF: 0.00224

Gnomad NFE exome AF: 0.00489

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.0111 AC: 15910 AN: 1434840 Hom.: 1472 Cov.: 34 AF XY: 0.00982 AC XY: 6967 AN XY: 709488

Gnomad4 AFR exome AF: 0.285

Gnomad4 AMR exome AF: 0.0156

Gnomad4 ASJ exome AF: 0.00110

Gnomad4 EAS exome AF: 0.000179

Gnomad4 SAS exome AF: 0.000446

Gnomad4 FIN exome AF: 0.00231

Gnomad4 NFE exome AF: 0.00412

Gnomad4 OTH exome AF: 0.0187

GnomAD4 genome AF: 0.0796 AC: 12123 AN: 152314 Hom.: 1549 Cov.: 34 AF XY: 0.0770 AC XY: 5736 AN XY: 74472

Gnomad4 AFR AF: 0.268

Gnomad4 AMR AF: 0.0309

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00491

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0380 Hom.: 120

Bravo AF: 0.0909

Asia WGS AF: 0.0170 AC: 61 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 04, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.3672-13G>A in intron 25 of PLEC: This variant is not expected to have clinical significance because it has been identified in 23.3% (896/3848) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs11991798). -

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

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.72
Dann	Benign	0.43
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.8

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: rs11991798; hg19: chr8-145002173;