9-127462281-G-C

Variant names:

• chr9-127462281-G-C
• rs555377969
• NM_001005373.4:c.436G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001384144.1(LRSAM1):​c.-349G>C variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRSAM1 NM_001384144.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.10
• Publications: 1 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: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023451656).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384144.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRSAM1	NM_001005373.4	MANE Select	c.436G>C	p.Val146Leu	missense	Exon 9 of 26	NP_001005373.1	Q6UWE0-1
	LRSAM1	NM_001384144.1		c.-349G>C		5_prime_UTR_premature_start_codon_gain	Exon 9 of 26	NP_001371073.1
	LRSAM1	NM_001005374.4		c.436G>C	p.Val146Leu	missense	Exon 8 of 25	NP_001005374.1	Q6UWE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRSAM1	ENST00000300417.11	TSL:1 MANE Select	c.436G>C	p.Val146Leu	missense	Exon 9 of 26	ENSP00000300417.6	Q6UWE0-1
	LRSAM1	ENST00000373322.1	TSL:1	c.436G>C	p.Val146Leu	missense	Exon 8 of 25	ENSP00000362419.1	Q6UWE0-1
	LRSAM1	ENST00000870574.1		c.436G>C	p.Val146Leu	missense	Exon 9 of 26	ENSP00000540633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease axonal type 2P (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0030
DANN	Benign	0.37
DEOGEN2	Benign	0.018	T
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.22	N
PhyloP100		-3.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.048
Sift	Benign	0.94	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.57		Gain of helix (P = 0.062)
MVP		0.20
MPC		0.17
ClinPred		0.020	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.022
gMVP		0.17
Mutation Taster		=99/1	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: rs555377969; hg19: chr9-130224560;