rs201387815
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_201384.3(PLEC):c.10499G>A(p.Arg3500His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0001 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3500C) has been classified as Likely benign.
Frequency
Consequence
NM_201384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEC | NM_201384.3 | c.10499G>A | p.Arg3500His | missense_variant | 32/32 | ENST00000345136.8 | |
PLEC | NM_201378.4 | c.10457G>A | p.Arg3486His | missense_variant | 32/32 | ENST00000356346.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.10499G>A | p.Arg3500His | missense_variant | 32/32 | 1 | NM_201384.3 | ||
PLEC | ENST00000356346.7 | c.10457G>A | p.Arg3486His | missense_variant | 32/32 | 1 | NM_201378.4 |
Frequencies
GnomAD3 genomes ? AF: 0.000250 AC: 38AN: 152226Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000100 AC: 25AN: 249406Hom.: 0 AF XY: 0.0000887 AC XY: 12AN XY: 135350
GnomAD4 exome AF: 0.0000848 AC: 124AN: 1461616Hom.: 0 Cov.: 76 AF XY: 0.0000770 AC XY: 56AN XY: 727134
GnomAD4 genome ? AF: 0.000250 AC: 38AN: 152226Hom.: 0 Cov.: 34 AF XY: 0.000269 AC XY: 20AN XY: 74374
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 16, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 28, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 17, 2022 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2021 | The c.10580G>A (p.R3527H) alteration is located in exon 33 (coding exon 32) of the PLEC gene. This alteration results from a G to A substitution at nucleotide position 10580, causing the arginine (R) at amino acid position 3527 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3527 of the PLEC protein (p.Arg3527His). This variant is present in population databases (rs201387815, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with PLEC-related conditions. ClinVar contains an entry for this variant (Variation ID: 478584). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLEC protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at