rs148059394

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6

The NM_001005373.4(LRSAM1):​c.586G>A​(p.Gly196Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000666 in 1,607,632 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 0.00045 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00069 ( 0 hom. )

Consequence

LRSAM1
NM_001005373.4 missense

Scores

8
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 5.87
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.30612838).
BP6
Variant 9-127467797-G-A is Benign according to our data. Variant chr9-127467797-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245644.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRSAM1NM_001005373.4 linkc.586G>A p.Gly196Ser missense_variant 10/26 ENST00000300417.11 NP_001005373.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRSAM1ENST00000300417.11 linkc.586G>A p.Gly196Ser missense_variant 10/261 NM_001005373.4 ENSP00000300417.6 Q6UWE0-1

Frequencies

GnomAD3 genomes
AF:
0.000447
AC:
68
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000289
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000485
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.000434
AC:
103
AN:
237504
Hom.:
0
AF XY:
0.000404
AC XY:
52
AN XY:
128594
show subpopulations
Gnomad AFR exome
AF:
0.000399
Gnomad AMR exome
AF:
0.00120
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000345
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000500
Gnomad OTH exome
AF:
0.000345
GnomAD4 exome
AF:
0.000689
AC:
1003
AN:
1455300
Hom.:
0
Cov.:
31
AF XY:
0.000699
AC XY:
506
AN XY:
723478
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.00100
Gnomad4 ASJ exome
AF:
0.0000387
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000118
Gnomad4 FIN exome
AF:
0.0000195
Gnomad4 NFE exome
AF:
0.000830
Gnomad4 OTH exome
AF:
0.000482
GnomAD4 genome
AF:
0.000446
AC:
68
AN:
152332
Hom.:
0
Cov.:
32
AF XY:
0.000430
AC XY:
32
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.00131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000485
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.000619
Hom.:
1
Bravo
AF:
0.000465
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.00130
AC:
5
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00116
AC:
10
ExAC
AF:
0.000371
AC:
45

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 20, 2024Reported previously as a variant of uncertain significance in two patients with a suspected diagnosis of Charcot-Marie-Tooth disease; however, clinical and segregation information was not provided (PMID: 32376792); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32376792) -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicOct 03, 2022- -
Charcot-Marie-Tooth disease axonal type 2P Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, London Health Sciences Centre-- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 09, 2023Unlikely 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.13
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;.;T;T
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.83
T;T;.;.
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.31
T;T;T;T
MetaSVM
Benign
-0.75
T
MutationAssessor
Uncertain
2.5
M;M;M;M
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-3.8
D;D;D;D
REVEL
Benign
0.27
Sift
Benign
0.055
T;T;T;T
Sift4G
Uncertain
0.025
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.81
MVP
0.66
MPC
0.67
ClinPred
0.089
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.31
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs148059394; hg19: chr9-130230076; COSMIC: COSV100031936; COSMIC: COSV100031936; API