NM_001005373.4:c.2041C>G

Variant names:

• chr9-127501138-C-G
• rs773899723
• NM_001005373.4:c.2041C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001005373.4(LRSAM1):​c.2041C>G​(p.Arg681Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R681Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRSAM1 NM_001005373.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.781
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31205845).

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.2041C>G	p.Arg681Gly	missense	Exon 25 of 26	NP_001005373.1
	LRSAM1	NM_001005374.4		c.2041C>G	p.Arg681Gly	missense	Exon 24 of 25	NP_001005374.1
	LRSAM1	NM_001384142.1		c.2041C>G	p.Arg681Gly	missense	Exon 25 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.2041C>G	p.Arg681Gly	missense	Exon 25 of 26	ENSP00000300417.6
	LRSAM1	ENST00000373322.1	TSL:1	c.2041C>G	p.Arg681Gly	missense	Exon 24 of 25	ENSP00000362419.1
	LRSAM1	ENST00000870574.1		c.2197C>G	p.Arg733Gly	missense	Exon 25 of 26	ENSP00000540633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	0.0043	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.78
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.33
Sift	Benign	0.093	T
Sift4G	Benign	0.15	T
Polyphen		0.25	B
Vest4		0.62
MutPred		0.27		Gain of sheet (P = 0.0166)
MVP		0.79
MPC		0.31
ClinPred		0.66	D
GERP RS		4.2
Varity_R		0.23
gMVP		0.66
Mutation Taster		=91/9	polymorphism

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: rs773899723; hg19: chr9-130263417;