rs140808447

Positions:

chr9-127502838-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6

The NM_001005373.4(LRSAM1):c.2111G>A(p.Arg704His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,611,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00059 ( 0 hom. )

Consequence

LRSAM1
NM_001005373.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.996

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 links:

LRSAM1 (HGNC:):

LRSAM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a zinc_finger_region RING-type (size 35) in uniprot entity LRSM1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001005373.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049303025).

BP6

Variant 9-127502838-G-A is Benign according to our data. Variant chr9-127502838-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472800.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRSAM1	NM_001005373.4 linkuse as main transcript	c.2111G>A	p.Arg704His	missense_variant	26/26	ENST00000300417.11	NP_001005373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRSAM1	ENST00000300417.11 linkuse as main transcript	c.2111G>A	p.Arg704His	missense_variant	26/26	1	NM_001005373.4	ENSP00000300417.6		Q6UWE0-1

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000408

AC:

100

AN:

245142

Hom.:

AF XY:

0.000337

AC XY:

AN XY:

133558

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00143

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000336

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.000586

AC:

855

AN:

1459746

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

410

AN XY:

726138

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.00128

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.000658

Gnomad4 OTH exome

AF:

0.000730

GnomAD4 genome

AF:

0.000361

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000350

Hom.:

Bravo

AF:

0.000450

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000475

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 28, 2019	- -

Charcot-Marie-Tooth disease axonal type 2P

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2021

Unlikely to be causative of LRSAM1-related Charcot-Marie-Tooth disease, type 2 (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.049

T;.;T;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.91

D;D;.;.

M_CAP

Benign

0.077

MetaRNN

Benign

0.049

T;T;T;T

MetaSVM

Uncertain

-0.029

MutationAssessor

Benign

1.8

L;.;L;L

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.94

N;N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.040

D;D;D;D

Sift4G

Uncertain

0.027

D;D;D;D

Polyphen

0.99

D;D;D;D

Vest4

0.16

MVP

0.82

MPC

0.26

ClinPred

0.016

GERP RS

4.5

Varity_R

0.068

gMVP

0.20

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over