rs150984897

Variant names:

• chr9-127502837-C-A
• rs150984897
• NM_001005373.4:c.2110C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-127502837-C-A
• chr9-127502837-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001005373.4(LRSAM1):​c.2110C>A​(p.Arg704Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R704H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LRSAM1 NM_001005373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001005373.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17345366).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRSAM1	NM_001005373.4	MANE Select	c.2110C>A	p.Arg704Ser	missense	Exon 26 of 26	NP_001005373.1	Q6UWE0-1
	LRSAM1	NM_001005374.4		c.2110C>A	p.Arg704Ser	missense	Exon 25 of 25	NP_001005374.1	Q6UWE0-1
	LRSAM1	NM_001384142.1		c.2110C>A	p.Arg704Ser	missense	Exon 26 of 26	NP_001371071.1	Q6UWE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRSAM1	ENST00000300417.11	TSL:1 MANE Select	c.2110C>A	p.Arg704Ser	missense	Exon 26 of 26	ENSP00000300417.6	Q6UWE0-1
	LRSAM1	ENST00000373322.1	TSL:1	c.2110C>A	p.Arg704Ser	missense	Exon 25 of 25	ENSP00000362419.1	Q6UWE0-1
	LRSAM1	ENST00000870574.1		c.2266C>A	p.Arg756Ser	missense	Exon 26 of 26	ENSP00000540633.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459804 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726174

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.0000224 AC: 1 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5582

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111600

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.20
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.096
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.77	N
PhyloP100		2.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.34
Sift	Benign	0.78	T
Sift4G	Benign	0.12	T
Polyphen		0.92	P
Vest4		0.22
MutPred		0.35		Gain of glycosylation at R704 (P = 0.02)
MVP		0.79
MPC		0.29
ClinPred		0.77	D
GERP RS		4.5
Varity_R		0.21
gMVP		0.31
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150984897; hg19: chr9-130265116;