rs150882646

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001005373.4(LRSAM1):c.1717C>A(p.Gln573Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,612,930 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q573H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 2 hom. )

Consequence

LRSAM1
NM_001005373.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.88

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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.078140885).

BP6

Variant 9-127495982-C-A is Benign according to our data. Variant chr9-127495982-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 472795.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRSAM1	NM_001005373.4 link	c.1717C>A	p.Gln573Lys	missense_variant	Exon 23 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.1717C>A	p.Gln573Lys	missense_variant	Exon 23 of 26	1	NM_001005373.4	ENSP00000300417.6		Q6UWE0-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000176

AC:

AN:

249440

AF XY:

0.000185

show subpopulations

Gnomad AFR exome

AF:

0.0000622

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

164

AN:

1460582

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

101

AN XY:

726578

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.000224

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000523

AC:

AN:

86114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52396

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000782

AC:

AN:

1111938

Other (OTH)

AF:

0.0000828

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41592

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000139

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 21, 2025

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.1717C>A (p.Gln573Lys) results in a conservative amino acid change located in the Sterile alpha motif domain (IPR001660) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 249440 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in LRSAM1 causing Charcot-Marie-Tooth disease axonal type 2P-AR (0.00018 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1717C>A 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: 472795). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Charcot-Marie-Tooth disease axonal type 2P

Uncertain:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 573 of the LRSAM1 protein (p.Gln573Lys). This variant is present in population databases (rs150882646, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with LRSAM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 472795). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LRSAM1 protein function with a negative predictive value of 80%. 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. -

not provided

Benign:1

Aug 26, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28335037) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.10

T;.;T;T

Eigen

Benign

0.086

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.86

D;D;.;.

M_CAP

Benign

0.027

MetaRNN

Benign

0.078

T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.1

M;.;M;M

PhyloP100

3.9

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.33

T;T;T;T

Sift4G

Benign

0.33

T;T;T;T

Polyphen

0.090

B;B;B;B

Vest4

0.38

MVP

0.78

MPC

0.25

ClinPred

0.027

GERP RS

5.8

Varity_R

0.081

gMVP

0.22

Mutation Taster

=91/9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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