rs1539567

Positions:

chr9-127479887-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001005373.4(LRSAM1):c.952A>G(p.Asn318Asp) variant causes a missense change. The variant allele was found at a frequency of 0.776 in 1,613,908 control chromosomes in the GnomAD database, including 488,141 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N318S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.75 ( 43334 hom., cov: 33)

Exomes 𝑓: 0.78 ( 444807 hom. )

Consequence

LRSAM1
NM_001005373.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 4.07

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.8612993E-7).

BP6

Variant 9-127479887-A-G is Benign according to our data. Variant chr9-127479887-A-G is described in ClinVar as [Benign]. Clinvar id is 365021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127479887-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRSAM1	NM_001005373.4 linkuse as main transcript	c.952A>G	p.Asn318Asp	missense_variant	14/26	ENST00000300417.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRSAM1	ENST00000300417.11 linkuse as main transcript	c.952A>G	p.Asn318Asp	missense_variant	14/26	1	NM_001005373.4	P1	Q6UWE0-1

Frequencies

GnomAD3 genomes

AF:

0.752

AC:

114292

AN:

152046

Hom.:

43298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.670

Gnomad AMI

AF:

0.687

Gnomad AMR

AF:

0.782

Gnomad ASJ

AF:

0.658

Gnomad EAS

AF:

0.681

Gnomad SAS

AF:

0.767

Gnomad FIN

AF:

0.872

Gnomad MID

AF:

0.726

Gnomad NFE

AF:

0.787

Gnomad OTH

AF:

0.739

GnomAD3 exomes

AF:

0.780

AC:

195492

AN:

250724

Hom.:

76927

AF XY:

0.778

AC XY:

105599

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.673

Gnomad AMR exome

AF:

0.857

Gnomad ASJ exome

AF:

0.659

Gnomad EAS exome

AF:

0.682

Gnomad SAS exome

AF:

0.770

Gnomad FIN exome

AF:

0.874

Gnomad NFE exome

AF:

0.783

Gnomad OTH exome

AF:

0.770

GnomAD4 exome

AF:

0.779

AC:

1138322

AN:

1461744

Hom.:

444807

Cov.:

AF XY:

0.778

AC XY:

565956

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.674

Gnomad4 AMR exome

AF:

0.850

Gnomad4 ASJ exome

AF:

0.654

Gnomad4 EAS exome

AF:

0.694

Gnomad4 SAS exome

AF:

0.773

Gnomad4 FIN exome

AF:

0.874

Gnomad4 NFE exome

AF:

0.783

Gnomad4 OTH exome

AF:

0.755

GnomAD4 genome

AF:

0.752

AC:

114383

AN:

152164

Hom.:

43334

Cov.:

AF XY:

0.755

AC XY:

56151

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.670

Gnomad4 AMR

AF:

0.782

Gnomad4 ASJ

AF:

0.658

Gnomad4 EAS

AF:

0.681

Gnomad4 SAS

AF:

0.767

Gnomad4 FIN

AF:

0.872

Gnomad4 NFE

AF:

0.787

Gnomad4 OTH

AF:

0.737

Alfa

AF:

0.768

Hom.:

109011

Bravo

AF:

0.742

TwinsUK

AF:

0.775

AC:

2874

ALSPAC

AF:

0.776

AC:

2991

ESP6500AA

AF:

0.682

AC:

3003

ESP6500EA

AF:

0.773

AC:

6642

ExAC

AF:

0.777

AC:

94310

Asia WGS

AF:

0.720

AC:

2506

AN:

3476

EpiCase

AF:

0.761

EpiControl

AF:

0.767

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2P

Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.41

DEOGEN2

Benign

0.028

T;.;T;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.13

T;T;.;.

MetaRNN

Benign

7.9e-7

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-2.0

N;N;N;N

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.37

PROVEAN

Benign

1.7

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.77

T;T;T;T

Sift4G

Benign

0.85

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.032

MPC

0.19

ClinPred

0.0098

GERP RS

5.9

Varity_R

0.076

gMVP

0.11

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