chr9-127502873-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001005373.4(LRSAM1):c.2146C>T(p.Arg716Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,607,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

LRSAM1
NM_001005373.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.71

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13087165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRSAM1	NM_001005373.4 link	c.2146C>T	p.Arg716Cys	missense_variant	Exon 26 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.2146C>T	p.Arg716Cys	missense_variant	Exon 26 of 26	1	NM_001005373.4	ENSP00000300417.6		Q6UWE0-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000170

AC:

AN:

235050

AF XY:

0.00000781

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000190

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000206

AC:

AN:

1454966

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

723404

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33324

American (AMR)

AF:

0.00

AC:

AN:

43966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25972

East Asian (EAS)

AF:

0.00

AC:

AN:

39358

South Asian (SAS)

AF:

0.0000821

AC:

AN:

85228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5380

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1109546

Other (OTH)

AF:

0.00

AC:

AN:

60078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The LRSAM1 p.Arg716Cys variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs772786050) and ClinVar (classified as a VUS by Invitae). The variant was also identified in control databases in 5 of 266350 chromosomes at a frequency of 0.000019 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 2 of 29184 chromosomes (freq: 0.000069), East Asian in 1 of 18898 chromosomes (freq: 0.000053) and European (non-Finnish) in 2 of 120682 chromosomes (freq: 0.000017), while the variant was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), and Other populations. The p.Arg716 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Mar 06, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Nov 27, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LRSAM1 c.2146C>T (p.Arg716Cys) results in a non-conservative amino acid change located in the Zinc/RING finger domain, C3HC4 (zinc finger) domain (IPR013083) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 235050 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2146C>T 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: 578379). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Jun 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2146C>T (p.R716C) alteration is located in exon 25 (coding exon 24) of the LRSAM1 gene. This alteration results from a C to T substitution at nucleotide position 2146, causing the arginine (R) at amino acid position 716 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease axonal type 2P

Uncertain:1

Mar 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LRSAM1 protein function. ClinVar contains an entry for this variant (Variation ID: 578379). This variant has not been reported in the literature in individuals affected with LRSAM1-related conditions. This variant is present in population databases (rs772786050, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 716 of the LRSAM1 protein (p.Arg716Cys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

T;.;T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.82

T;T;.;.

M_CAP

Benign

0.048

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.7

M;.;M;M

PhyloP100

1.7

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Benign

0.11

Sift

Benign

0.031

D;D;D;D

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.0090

B;B;B;B

Vest4

0.15

MutPred

0.53

Gain of helix (P = 0.027);.;Gain of helix (P = 0.027);Gain of helix (P = 0.027);

MVP

0.68

MPC

0.24

ClinPred

0.76

GERP RS

0.39

Varity_R

0.15

gMVP

0.62

Mutation Taster

=78/22

polymorphism

(source)

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

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chr9-127502873-C-T

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