9-127479848-C-G

Variant names:

• chr9-127479848-C-G
• rs376566243
• NM_001005373.4:c.913C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001005373.4(LRSAM1):​c.913C>G​(p.Arg305Gly) 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 pathogenic 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. R305Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: LRSAM1 NM_001005373.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.748

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.913C>G	p.Arg305Gly	missense	Exon 14 of 26	NP_001005373.1
	LRSAM1	NM_001005374.4		c.913C>G	p.Arg305Gly	missense	Exon 13 of 25	NP_001005374.1
	LRSAM1	NM_001384142.1		c.913C>G	p.Arg305Gly	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.913C>G	p.Arg305Gly	missense	Exon 14 of 26	ENSP00000300417.6
	LRSAM1	ENST00000373322.1	TSL:1	c.913C>G	p.Arg305Gly	missense	Exon 13 of 25	ENSP00000362419.1
	LRSAM1	ENST00000676170.1		c.913C>G	p.Arg305Gly	missense	Exon 14 of 27	ENSP00000502177.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.063	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.1
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.26
Sift	Benign	0.056	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.23		Gain of glycosylation at S304 (P = 0.0484)
MVP		0.88
MPC		0.72
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.53
gMVP		0.41
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs376566243; hg19: chr9-130242127;