rs75690855

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001384144.1(LRSAM1):​c.-237C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00596 in 1,610,262 control chromosomes in the GnomAD database, including 459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 256 hom., cov: 32)
Exomes 𝑓: 0.0033 ( 203 hom. )

Consequence

LRSAM1
NM_001384144.1 5_prime_UTR_premature_start_codon_gain

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0580
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0026407242).
BP6
Variant 9-127467759-C-T is Benign according to our data. Variant chr9-127467759-C-T is described in ClinVar as [Benign]. Clinvar id is 365014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127467759-C-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
LRSAM1NM_001005373.4 linkuse as main transcriptc.548C>T p.Ser183Leu missense_variant 10/26 ENST00000300417.11 NP_001005373.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
LRSAM1ENST00000300417.11 linkuse as main transcriptc.548C>T p.Ser183Leu missense_variant 10/261 NM_001005373.4 ENSP00000300417.6 Q6UWE0-1

Frequencies

GnomAD3 genomes
AF:
0.0314
AC:
4779
AN:
152222
Hom.:
254
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.109
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0107
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000514
Gnomad OTH
AF:
0.0263
GnomAD3 exomes
AF:
0.00798
AC:
1928
AN:
241554
Hom.:
102
AF XY:
0.00567
AC XY:
743
AN XY:
130944
show subpopulations
Gnomad AFR exome
AF:
0.112
Gnomad AMR exome
AF:
0.00399
Gnomad ASJ exome
AF:
0.000206
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000675
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000403
Gnomad OTH exome
AF:
0.00446
GnomAD4 exome
AF:
0.00329
AC:
4797
AN:
1457922
Hom.:
203
Cov.:
31
AF XY:
0.00281
AC XY:
2035
AN XY:
724972
show subpopulations
Gnomad4 AFR exome
AF:
0.113
Gnomad4 AMR exome
AF:
0.00503
Gnomad4 ASJ exome
AF:
0.0000386
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000117
Gnomad4 FIN exome
AF:
0.0000190
Gnomad4 NFE exome
AF:
0.000353
Gnomad4 OTH exome
AF:
0.00613
GnomAD4 genome
AF:
0.0315
AC:
4795
AN:
152340
Hom.:
256
Cov.:
32
AF XY:
0.0302
AC XY:
2252
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.109
Gnomad4 AMR
AF:
0.0107
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000514
Gnomad4 OTH
AF:
0.0260
Alfa
AF:
0.00575
Hom.:
60
Bravo
AF:
0.0362
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.111
AC:
488
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.00994
AC:
1206
Asia WGS
AF:
0.00462
AC:
16
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2P Benign:3
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 06, 2023- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Charcot-Marie-Tooth disease Benign:1
Benign, criteria provided, single submitterclinical testingMolecular Genetics Laboratory, London Health Sciences Centre-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
14
DANN
Benign
0.87
DEOGEN2
Benign
0.066
T;.;T;T
Eigen
Benign
-0.92
Eigen_PC
Benign
-0.92
FATHMM_MKL
Benign
0.033
N
LIST_S2
Benign
0.82
T;T;.;.
MetaRNN
Benign
0.0026
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.64
N;N;N;N
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.9
N;N;N;N
REVEL
Benign
0.043
Sift
Benign
0.34
T;T;T;T
Sift4G
Benign
0.11
T;T;T;T
Polyphen
0.0
B;B;B;B
Vest4
0.36
MVP
0.43
MPC
0.15
ClinPred
0.0034
T
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.031
gMVP
0.26

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: rs75690855; hg19: chr9-130230038; API