9-127479887-A-G

Variant names:

• chr9-127479887-A-G
• rs1539567
• NM_001005373.4:c.952A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N318H) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.07
• Publications: 38 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2P

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 365021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005373.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRSAM1	NM_001005373.4	MANE Select	c.952A>G	p.Asn318Asp	missense	Exon 14 of 26	NP_001005373.1
	LRSAM1	NM_001005374.4		c.952A>G	p.Asn318Asp	missense	Exon 13 of 25	NP_001005374.1
	LRSAM1	NM_001384142.1		c.952A>G	p.Asn318Asp	missense	Exon 14 of 26	NP_001371071.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRSAM1	ENST00000300417.11	TSL:1 MANE Select	c.952A>G	p.Asn318Asp	missense	Exon 14 of 26	ENSP00000300417.6
	LRSAM1	ENST00000373322.1	TSL:1	c.952A>G	p.Asn318Asp	missense	Exon 13 of 25	ENSP00000362419.1
	LRSAM1	ENST00000676170.1		c.952A>G	p.Asn318Asp	missense	Exon 14 of 27	ENSP00000502177.1

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114292 AN: 152046 Hom.: 43298 Cov.: 33

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

GnomAD2 exomes AF: 0.780 AC: 195492 AN: 250724 AF XY: 0.778

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 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.: 67 AF XY: 0.778 AC XY: 565956 AN XY: 727178

African (AFR) AF: 0.674 AC: 22565 AN: 33480

American (AMR) AF: 0.850 AC: 38028 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 17086 AN: 26134

East Asian (EAS) AF: 0.694 AC: 27549 AN: 39692

South Asian (SAS) AF: 0.773 AC: 66687 AN: 86252

European-Finnish (FIN) AF: 0.874 AC: 46638 AN: 53350

Middle Eastern (MID) AF: 0.698 AC: 4025 AN: 5768

European-Non Finnish (NFE) AF: 0.783 AC: 870137 AN: 1111956

Other (OTH) AF: 0.755 AC: 45607 AN: 60390

GnomAD4 genome AF: 0.752 AC: 114383 AN: 152164 Hom.: 43334 Cov.: 33 AF XY: 0.755 AC XY: 56151 AN XY: 74392

African (AFR) AF: 0.670 AC: 27786 AN: 41488

American (AMR) AF: 0.782 AC: 11965 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 2284 AN: 3472

East Asian (EAS) AF: 0.681 AC: 3507 AN: 5152

South Asian (SAS) AF: 0.767 AC: 3701 AN: 4828

European-Finnish (FIN) AF: 0.872 AC: 9248 AN: 10600

Middle Eastern (MID) AF: 0.736 AC: 215 AN: 292

European-Non Finnish (NFE) AF: 0.787 AC: 53494 AN: 68008

Other (OTH) AF: 0.737 AC: 1558 AN: 2114

Alfa AF: 0.769 Hom.: 193711

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2P Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charcot-Marie-Tooth disease Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.41
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	7.9e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.0	N
PhyloP100		4.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.15
Sift	Benign	0.77	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.032
MPC		0.19
ClinPred		0.0098	T
GERP RS		5.9
Varity_R		0.076
gMVP		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1539567; hg19: chr9-130242166; COSMIC: COSV55938948; COSMIC: COSV55938948;