NM_001005373.4:c.965A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001005373.4(LRSAM1):c.965A>G(p.Gln322Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,611,996 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 39 hom. )

Consequence

LRSAM1
NM_001005373.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 2.60

Publications

7 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

LRSAM1 links:

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=0.0072479546).

BP6

Variant 9-127479900-A-G is Benign according to our data. Variant chr9-127479900-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00338 (515/152322) while in subpopulation SAS AF = 0.00807 (39/4830). AF 95% confidence interval is 0.00607. There are 3 homozygotes in GnomAd4. There are 244 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRSAM1	NM_001005373.4 link	c.965A>G	p.Gln322Arg	missense_variant	Exon 14 of 26	ENST00000300417.11	NP_001005373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRSAM1	ENST00000300417.11 link	c.965A>G	p.Gln322Arg	missense_variant	Exon 14 of 26	1	NM_001005373.4	ENSP00000300417.6		Q6UWE0-1

Frequencies

GnomAD3 genomes

AF:

0.00339

AC:

516

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00530

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00848

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00412

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00384

AC:

953

AN:

248064

AF XY:

0.00424

show subpopulations

Gnomad AFR exome

AF:

0.000647

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.00691

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.00406

Gnomad NFE exome

AF:

0.00408

Gnomad OTH exome

AF:

0.00347

GnomAD4 exome

AF:

0.00506

AC:

7385

AN:

1459674

Hom.:

Cov.:

AF XY:

0.00518

AC XY:

3759

AN XY:

726204

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33446

American (AMR)

AF:

0.00146

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00731

AC:

191

AN:

26126

East Asian (EAS)

AF:

0.000126

AC:

AN:

39668

South Asian (SAS)

AF:

0.00831

AC:

716

AN:

86172

European-Finnish (FIN)

AF:

0.00422

AC:

223

AN:

52872

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00527

AC:

5858

AN:

1110728

Other (OTH)

AF:

0.00481

AC:

290

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

432

864

1295

1727

2159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

228

456

684

912

1140

<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:

0.00338

AC:

515

AN:

152322

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

244

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41576

American (AMR)

AF:

0.00529

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00807

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00413

AC:

281

AN:

68030

Other (OTH)

AF:

0.00427

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00413

Hom.:

Bravo

AF:

0.00306

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00367

AC:

445

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00447

EpiControl

AF:

0.00385

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LRSAM1: BP4, BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 21, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2P

Benign:3Other:1

Jan 12, 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 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 23, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not specified

Benign:2

Jun 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LRSAM1 c.965A>G (p.Gln322Arg) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant allele was found at a frequency of 0.0038 in 248064 control chromosomes, predominantly at a frequency of 0.0083 within the South Asian subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7.42 fold of the estimated maximal expected allele frequency for a pathogenic variant in LRSAM1 causing Charcot-Marie-Tooth disease axonal type 2P-AR phenotype (0.0011). To our knowledge, no occurrence of c.965A>G in individuals affected with Charcot-Marie-Tooth disease axonal type 2P-AR and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 241839). Based on the evidence outlined above, the variant was classified as likely benign. -

Jul 27, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 28, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.064

T;.;T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.077

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.59

T;T;.;.

M_CAP

Benign

0.0061

MetaRNN

Benign

0.0072

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;M;M;M

PhyloP100

2.6

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.062

Sift

Benign

0.67

T;T;T;T

Sift4G

Benign

0.33

T;D;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.079

MVP

0.55

MPC

0.18

ClinPred

0.014

GERP RS

3.4

Varity_R

0.10

gMVP

0.17

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over