NM_001005373.4:c.548C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001005373.4(LRSAM1):​c.548C>T​(p.Ser183Leu) variant causes a missense 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S183S) has been classified as Likely benign.

Frequency

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

Consequence

LRSAM1
NM_001005373.4 missense

Scores

18

Clinical Significance

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

Conservation

PhyloP100: 0.0580

Publications

6 publications found
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]
LRSAM1 Gene-Disease associations (from GenCC):
  • Charcot-Marie-Tooth disease axonal type 2P
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.
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 rank MANE Protein UniProt
LRSAM1NM_001005373.4 linkc.548C>T p.Ser183Leu missense_variant Exon 10 of 26 ENST00000300417.11 NP_001005373.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LRSAM1ENST00000300417.11 linkc.548C>T p.Ser183Leu missense_variant Exon 10 of 26 1 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
GnomAD2 exomes
AF:
0.00798
AC:
1928
AN:
241554
AF XY:
0.00567
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 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
African (AFR)
AF:
0.113
AC:
3774
AN:
33462
American (AMR)
AF:
0.00503
AC:
223
AN:
44308
Ashkenazi Jewish (ASJ)
AF:
0.0000386
AC:
1
AN:
25916
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39600
South Asian (SAS)
AF:
0.000117
AC:
10
AN:
85428
European-Finnish (FIN)
AF:
0.0000190
AC:
1
AN:
52502
Middle Eastern (MID)
AF:
0.00469
AC:
27
AN:
5754
European-Non Finnish (NFE)
AF:
0.000353
AC:
392
AN:
1110754
Other (OTH)
AF:
0.00613
AC:
369
AN:
60198
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
261
523
784
1046
1307
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
120
240
360
480
600
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
African (AFR)
AF:
0.109
AC:
4539
AN:
41564
American (AMR)
AF:
0.0107
AC:
164
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.000514
AC:
35
AN:
68038
Other (OTH)
AF:
0.0260
AC:
55
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
223
446
669
892
1115
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
48
96
144
192
240
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0117
Hom.:
192
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
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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 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. -

Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 06, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease Benign:1
-
Molecular Genetics Laboratory, London Health Sciences Centre
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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
PhyloP100
0.058
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
Mutation Taster
=99/1
polymorphism (auto)

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

Other links and lift over

dbSNP: rs75690855; hg19: chr9-130230038; API