rs765956865
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6
The NM_001005373.4(LRSAM1):c.2062C>A(p.Leu688Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,612,744 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
LRSAM1
NM_001005373.4 missense
NM_001005373.4 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 2.17
Genes affected
LRSAM1 (HGNC:25135): (leucine rich repeat and sterile alpha motif containing 1) This gene encodes a ring finger protein involved in a variety of functions, including regulation of signaling pathways and cell adhesion, mediation of self-ubiquitylation, and involvement in cargo sorting during receptor endocytosis. Mutations in this gene have been associated with Charcot-Marie-Tooth disease. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jan 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001005373.4
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.05755794).
BP6
?
Variant 9-127502789-C-A is Benign according to our data. Variant chr9-127502789-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408268.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRSAM1 | NM_001005373.4 | c.2062C>A | p.Leu688Ile | missense_variant | 26/26 | ENST00000300417.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRSAM1 | ENST00000300417.11 | c.2062C>A | p.Leu688Ile | missense_variant | 26/26 | 1 | NM_001005373.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152100Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000234 AC: 58AN: 247492Hom.: 0 AF XY: 0.000156 AC XY: 21AN XY: 134566
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GnomAD4 exome AF: 0.0000493 AC: 72AN: 1460644Hom.: 0 Cov.: 34 AF XY: 0.0000413 AC XY: 30AN XY: 726608
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152100Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74314
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2020 | The p.L688I variant (also known as c.2062C>A), located in coding exon 24 of the LRSAM1 gene, results from a C to A substitution at nucleotide position 2062. The leucine at codon 688 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on population data from Genome Aggregation Consortium (gnomAD), the p.L688I variant has an overall frequency of 0.02116% (59/278788 total alleles studied) without any homozygous individuals observed. The highest observed sub-population frequency was 0.1616% (57/35264 total alleles studied) in the Latino cochort. Therefore, this variant is considered to be likely benign for dominantly inherited LRSAM1-related neuropathy but is still rare enough to potentially be disease causing for recessively inherited LRSAM1-related neuropathy. Since supporting evidence for recessive neuropathy is limited at this time, the clinical significance of this alteration remains unclear. - |
Charcot-Marie-Tooth disease axonal type 2P Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 14, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;.;.
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;L;L
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
P;P;P;P
Vest4
MutPred
Loss of helix (P = 0.0033);.;Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);
MVP
MPC
0.60
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at