rs140808447

chr9-127502838-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R704C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00059 (0 hom.)
• Consequence: LRSAM1 NM_001005373.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.996

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 -1 ACMG points.

• PM1: In a zinc_finger_region RING-type (size 35) in uniprot entity LRSM1_HUMAN there are 16 pathogenic changes around while only 3 benign (84%) 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	UniProt
LRSAM1	NM_001005373.4	c.2111G>A	p.Arg704His	missense_variant	26/26	ENST00000300417.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRSAM1	ENST00000300417.11	c.2111G>A	p.Arg704His	missense_variant	26/26	1	NM_001005373.4	P1

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152128 Hom.: 0 Cov.: 31

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.: 0 AF XY: 0.000337 AC XY: 45 AN XY: 133558

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.: 0 Cov.: 34 AF XY: 0.000565 AC XY: 410 AN XY: 726138

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: 55 AN: 152246 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74422

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.: 0

Bravo AF: 0.000450

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000654

EpiControl AF: 0.000475

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

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

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	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	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	23
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	D
LIST_S2	Uncertain	0.91	D;D;.;.
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.049	T;T;T;T
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Benign	1.8	L;.;L;L
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Benign	0.46	T
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	T
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

Other links and lift over

dbSNP: rs140808447; hg19: chr9-130265117;