rs78461695

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_201384.3(PLEC):​c.11720C>T​(p.Thr3907Met) variant causes a missense change. The variant allele was found at a frequency of 0.00926 in 1,596,684 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 6 hom., cov: 32)
Exomes 𝑓: 0.0094 ( 69 hom. )

Consequence

PLEC
NM_201384.3 missense

Scores

8
10

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.10
Variant links:
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 These names were superseded by plectin.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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0072327554).
BP6
Variant 8-143918101-G-A is Benign according to our data. Variant chr8-143918101-G-A is described in ClinVar as [Benign]. Clinvar id is 196812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143918101-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00765 (1165/152272) while in subpopulation AMR AF= 0.0133 (203/15308). AF 95% confidence interval is 0.0118. There are 6 homozygotes in gnomad4. There are 516 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PLECNM_201384.3 linkc.11720C>T p.Thr3907Met missense_variant 32/32 ENST00000345136.8 NP_958786.1 Q15149-4
PLECNM_201378.4 linkc.11678C>T p.Thr3893Met missense_variant 32/32 ENST00000356346.7 NP_958780.1 Q15149-9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PLECENST00000345136.8 linkc.11720C>T p.Thr3907Met missense_variant 32/321 NM_201384.3 ENSP00000344848.3 Q15149-4
PLECENST00000356346.7 linkc.11678C>T p.Thr3893Met missense_variant 32/321 NM_201378.4 ENSP00000348702.3 Q15149-9

Frequencies

GnomAD3 genomes
AF:
0.00766
AC:
1165
AN:
152154
Hom.:
6
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00212
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0133
Gnomad ASJ
AF:
0.00634
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.00339
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0116
Gnomad OTH
AF:
0.00860
GnomAD3 exomes
AF:
0.00775
AC:
1690
AN:
218106
Hom.:
9
AF XY:
0.00762
AC XY:
919
AN XY:
120592
show subpopulations
Gnomad AFR exome
AF:
0.00204
Gnomad AMR exome
AF:
0.00897
Gnomad ASJ exome
AF:
0.00564
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00220
Gnomad FIN exome
AF:
0.00434
Gnomad NFE exome
AF:
0.0115
Gnomad OTH exome
AF:
0.0117
GnomAD4 exome
AF:
0.00943
AC:
13626
AN:
1444412
Hom.:
69
Cov.:
57
AF XY:
0.00923
AC XY:
6631
AN XY:
718258
show subpopulations
Gnomad4 AFR exome
AF:
0.00150
Gnomad4 AMR exome
AF:
0.00924
Gnomad4 ASJ exome
AF:
0.00503
Gnomad4 EAS exome
AF:
0.0000763
Gnomad4 SAS exome
AF:
0.00230
Gnomad4 FIN exome
AF:
0.00475
Gnomad4 NFE exome
AF:
0.0109
Gnomad4 OTH exome
AF:
0.00936
GnomAD4 genome
AF:
0.00765
AC:
1165
AN:
152272
Hom.:
6
Cov.:
32
AF XY:
0.00693
AC XY:
516
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00212
Gnomad4 AMR
AF:
0.0133
Gnomad4 ASJ
AF:
0.00634
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.000830
Gnomad4 FIN
AF:
0.00339
Gnomad4 NFE
AF:
0.0116
Gnomad4 OTH
AF:
0.00851
Alfa
AF:
0.00945
Hom.:
3
Bravo
AF:
0.00793
TwinsUK
AF:
0.0116
AC:
43
ALSPAC
AF:
0.00778
AC:
30
ESP6500AA
AF:
0.000730
AC:
3
ESP6500EA
AF:
0.0107
AC:
90
ExAC
AF:
0.00723
AC:
870
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsAug 29, 2018- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2024PLEC: BP4, BS1, BS2 -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not specified Benign:3
Benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of ChicagoJun 27, 2022- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 06, 2015- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 11, 2016This 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. -
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
24
DANN
Benign
0.95
DEOGEN2
Benign
0.32
.;.;.;.;T;.;.;.;.;.
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D;D;D;D
MetaRNN
Benign
0.0072
T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.31
T
MutationAssessor
Uncertain
2.5
.;.;.;.;M;.;.;.;.;.
PrimateAI
Benign
0.44
T
PROVEAN
Uncertain
-2.8
D;D;D;D;D;D;D;D;.;D
REVEL
Benign
0.28
Sift
Uncertain
0.018
D;D;D;D;D;D;D;D;.;D
Sift4G
Uncertain
0.033
D;D;D;D;D;D;D;D;.;D
Polyphen
1.0
D;D;D;D;D;D;D;D;.;.
Vest4
0.32
MVP
0.77
ClinPred
0.016
T
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.11
gMVP
0.64

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs78461695; hg19: chr8-144992269; API