rs200361523
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_201384.3(PLEC):c.13111G>A(p.Ala4371Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000558 in 1,612,634 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. A4371V) has been classified as Uncertain significance.
Frequency
Consequence
NM_201384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEC | NM_201384.3 | c.13111G>A | p.Ala4371Thr | missense_variant | 32/32 | ENST00000345136.8 | |
PLEC | NM_201378.4 | c.13069G>A | p.Ala4357Thr | missense_variant | 32/32 | ENST00000356346.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.13111G>A | p.Ala4371Thr | missense_variant | 32/32 | 1 | NM_201384.3 | ||
PLEC | ENST00000356346.7 | c.13069G>A | p.Ala4357Thr | missense_variant | 32/32 | 1 | NM_201378.4 |
Frequencies
GnomAD3 genomes ? AF: 0.000401 AC: 61AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000347 AC: 86AN: 247494Hom.: 0 AF XY: 0.000408 AC XY: 55AN XY: 134826
GnomAD4 exome AF: 0.000574 AC: 839AN: 1460472Hom.: 1 Cov.: 44 AF XY: 0.000601 AC XY: 437AN XY: 726546
GnomAD4 genome ? AF: 0.000401 AC: 61AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32AN XY: 74340
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 03, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 01, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 04, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 01, 2019 | This variant is associated with the following publications: (PMID: 28492532) - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2021 | The c.13192G>A (p.A4398T) 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 13192, causing the alanine (A) at amino acid position 4398 to be replaced by a threonine (T). 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 04, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4398 of the PLEC protein (p.Ala4398Thr). This variant is present in population databases (rs200361523, gnomAD 0.1%). 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: 196853). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PLEC protein function. 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