12-65238526-A-G
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_014319.5(LEMD3):c.1720A>G(p.Ile574Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000816 in 1,604,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I574M) has been classified as Uncertain significance.
Frequency
Consequence
NM_014319.5 missense
Scores
Clinical Significance
Conservation
Publications
- Buschke-Ollendorff syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
- isolated osteopoikilosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- melorheostosis with osteopoikilosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LEMD3 | NM_014319.5 | c.1720A>G | p.Ile574Val | missense_variant | Exon 5 of 13 | ENST00000308330.3 | NP_055134.2 | |
LEMD3 | NM_001167614.2 | c.1717A>G | p.Ile573Val | missense_variant | Exon 5 of 13 | NP_001161086.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152188Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000956 AC: 24AN: 251018 AF XY: 0.000103 show subpopulations
GnomAD4 exome AF: 0.0000847 AC: 123AN: 1452600Hom.: 0 Cov.: 29 AF XY: 0.0000871 AC XY: 63AN XY: 723298 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74354 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Dermatofibrosis lenticularis disseminata Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 574 of the LEMD3 protein (p.Ile574Val). This variant is present in population databases (rs374107839, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LEMD3-related conditions. ClinVar contains an entry for this variant (Variation ID: 310239). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LEMD3 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