rs140786088

Positions:

chr9-127501072-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001005373.4(LRSAM1):c.1975G>A(p.Val659Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,614,008 control chromosomes in the GnomAD database, including 47 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 37 hom. )

Consequence

LRSAM1
NM_001005373.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.864

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034552217).

BP6

Variant 9-127501072-G-A is Benign according to our data. Variant chr9-127501072-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 246184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00342 (521/152284) while in subpopulation EAS AF= 0.00775 (40/5162). AF 95% confidence interval is 0.00585. There are 10 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRSAM1	NM_001005373.4 linkuse as main transcript	c.1975G>A	p.Val659Met	missense_variant	25/26	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.1975G>A	p.Val659Met	missense_variant	25/26	1	NM_001005373.4	ENSP00000300417.6		Q6UWE0-1

Frequencies

GnomAD3 genomes

AF:

0.00342

AC:

520

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.00754

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0380

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00447

AC:

1124

AN:

251252

Hom.:

AF XY:

0.00432

AC XY:

587

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00245

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.0376

Gnomad NFE exome

AF:

0.00167

Gnomad OTH exome

AF:

0.00506

GnomAD4 exome

AF:

0.00216

AC:

3163

AN:

1461724

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

1544

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00379

Gnomad4 EAS exome

AF:

0.0122

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.0358

Gnomad4 NFE exome

AF:

0.000452

Gnomad4 OTH exome

AF:

0.00245

GnomAD4 genome

AF:

0.00342

AC:

521

AN:

152284

Hom.:

Cov.:

AF XY:

0.00508

AC XY:

378

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.00775

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0380

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000860

Hom.:

Bravo

AF:

0.000574

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00406

AC:

493

Asia WGS

AF:

0.00895

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2P

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 14, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

LRSAM1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.060

T;.;T;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.66

T;T;.;.

MetaRNN

Benign

0.0035

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.63

N;.;N;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.86

N;N;N;N

REVEL

Benign

0.016

Sift

Benign

0.11

T;T;T;T

Sift4G

Benign

0.27

T;T;T;T

Polyphen

0.014

B;B;B;B

Vest4

0.27

MVP

0.28

MPC

0.18

ClinPred

0.010

GERP RS

3.3

Varity_R

0.040

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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