9-127497299-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001005373.4(LRSAM1):c.1877T>G(p.Val626Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,612,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LRSAM1 | NM_001005373.4 | c.1877T>G | p.Val626Gly | missense_variant | Exon 24 of 26 | ENST00000300417.11 | NP_001005373.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 151918Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250554Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135576
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1460664Hom.: 0 Cov.: 31 AF XY: 0.0000317 AC XY: 23AN XY: 726662
GnomAD4 genome AF: 0.0000395 AC: 6AN: 152038Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74308
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The p.V626G variant (also known as c.1877T>G), located in coding exon 22 of the LRSAM1 gene, results from a T to G substitution at nucleotide position 1877. The valine at codon 626 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
The V626G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project and was not observed with any significant frequency in the 1000 Genomes Project. The V626G variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. Additionally, missense variants in the LRSAM1 gene have not been reported in association with neuropathy (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Charcot-Marie-Tooth disease axonal type 2P Uncertain:1
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 626 of the LRSAM1 protein (p.Val626Gly). This variant is present in population databases (rs574202204, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of LRSAM1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 234883). 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 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at