rs756880678

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001005373.4(LRSAM1):c.1913-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000018 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

LRSAM1
NM_001005373.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 4.20

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.8, offset of 2, new splice context is: tctgtctggtccccacaaAGctg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-127501009-G-A is Pathogenic according to our data. Variant chr9-127501009-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 204301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127501009-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRSAM1	NM_001005373.4 link	c.1913-1G>A		splice_acceptor_variant, intron_variant	Intron 24 of 25	ENST00000300417.11	NP_001005373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRSAM1	ENST00000300417.11 link	c.1913-1G>A		splice_acceptor_variant, intron_variant	Intron 24 of 25	1	NM_001005373.4	ENSP00000300417.6		Q6UWE0-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152148

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251272

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135862

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Pathogenic:1Uncertain:1

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Apr 09, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1913-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 23 of the LRSAM1 gene. This variant was found to segregate with autosomal recessive Charcot-Marie-Tooth disease, type 2P (CMT2P) in one family. Additionally, RNA studies demonstrated that this alteration results in a transcript expected to trigger nonsense-mediated mRNA decay (Guernsey DL et al. PLoS Genet, 2010 Aug;6). Based on the supporting evidence, this variant is expected to be causative of autosomal recessive CMT2P. However, loss of function of LRSAM1 has not been established as a mechanism of disease for autosomal dominant CMT2P, so the clinical significance for autosomal dominant CMT2P is unclear. -

not provided

Pathogenic:1

Aug 04, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the LRSAM1 gene demonstrated a sequence change in the canonical splice acceptor site of intron 23, c.1913-1G>A. This pathogenic sequence change is predicted to disrupt RNA splicing and likely to result in an absent or disrupted protein product (PMID: 20865121). This sequence change has been described in the gnomAD database with a low frequency of 0.005% in the European sub-population (dbSNP rs756880678). The majority of pathogenic variants in LRSAM1 are present in the heterozygous state and cause an autosomal dominant phenotype. However, this sequence change has been previously reported in the homozygous state segregating with disease in six affected individuals from one consanguineous family (PMID: 20865121). -

Charcot-Marie-Tooth disease axonal type 2P

Pathogenic:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 23 of the LRSAM1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs756880678, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 20865121). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 204301). Studies have shown that disruption of this splice site results in altered splicing, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20865121). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.84

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.87

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.76

Position offset: 3

DS_AL_spliceai

0.99

Position offset: 1

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