rs373570877

Positions:

• chr9-127483014-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001005373.4(LRSAM1):​c.1153G>A​(p.Val385Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000842 in 1,604,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.000098 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: LRSAM1 NM_001005373.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 2.48

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024876714).
• BP6: Variant 9-127483014-G-A is Benign according to our data. Variant chr9-127483014-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 578496.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRSAM1	NM_001005373.4	c.1153G>A	p.Val385Ile	missense_variant	16/26	ENST00000300417.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRSAM1	ENST00000300417.11	c.1153G>A	p.Val385Ile	missense_variant	16/26	1	NM_001005373.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152220 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000906 AC: 21 AN: 231714 Hom.: 0 AF XY: 0.0000959 AC XY: 12 AN XY: 125184

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000116

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000863

Gnomad OTH exome AF: 0.000700

GnomAD4 exome AF: 0.0000827 AC: 120 AN: 1451768 Hom.: 0 Cov.: 31 AF XY: 0.0000790 AC XY: 57 AN XY: 721204

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.000140

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0000710

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000713

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152338 Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 7 AN XY: 74490

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000908 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2022	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	LRSAM1: PM2, BP4 -

Charcot-Marie-Tooth disease axonal type 2P Uncertain:1 Benign:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 385 of the LRSAM1 protein (p.Val385Ile). This variant is present in population databases (rs373570877, gnomAD 0.02%). 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: 578496). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.066	T;.;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.74	T;T;.;.
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.025	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.59	N;N;N;N
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.32	N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.39	T;T;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.18
MVP		0.60
MPC		0.14
ClinPred		0.028	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.013
gMVP		0.24

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

Other links and lift over

dbSNP: rs373570877; hg19: chr9-130245293; COSMIC: COSV55939826;