chr9-127502837-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_001005373.4(LRSAM1):c.2110C>T(p.Arg704Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000924 in 1,612,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001005373.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LRSAM1 | NM_001005373.4 | c.2110C>T | p.Arg704Cys | missense_variant | Exon 26 of 26 | ENST00000300417.11 | NP_001005373.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152200Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000102 AC: 25AN: 245216Hom.: 0 AF XY: 0.0000823 AC XY: 11AN XY: 133618
GnomAD4 exome AF: 0.0000918 AC: 134AN: 1459804Hom.: 0 Cov.: 34 AF XY: 0.0000812 AC XY: 59AN XY: 726174
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152200Hom.: 0 Cov.: 31 AF XY: 0.0000941 AC XY: 7AN XY: 74352
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2P Uncertain:3
The LRSAM1 c.2110C>T; p.Arg704Cys variant (rs150984897), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 539996). This variant is found in the general population with an overall allele frequency of 0.0105% (29/276,564 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.61). Due to limited information, the clinical significance of this variant is uncertain at this time. -
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 704 of the LRSAM1 protein (p.Arg704Cys). This variant is present in population databases (rs150984897, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with LRSAM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 539996). 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 LRSAM1 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. -
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:2
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Inborn genetic diseases Uncertain:1
Unlikely to be causative of LRSAM1-related Charcot-Marie-Tooth disease, type 2 (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at