rs751593173

Variant names:

• chr9-127489448-C-T
• rs751593173
• NM_001005373.4:c.1352C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001005373.4(LRSAM1):​c.1352C>T​(p.Ala451Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,606,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A451T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: LRSAM1 NM_001005373.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 1.96
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042336464).

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.1352C>T	p.Ala451Val	missense	Exon 19 of 26	NP_001005373.1
	LRSAM1	NM_001005374.4		c.1352C>T	p.Ala451Val	missense	Exon 18 of 25	NP_001005374.1
	LRSAM1	NM_001384142.1		c.1352C>T	p.Ala451Val	missense	Exon 19 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.1352C>T	p.Ala451Val	missense	Exon 19 of 26	ENSP00000300417.6
	LRSAM1	ENST00000373322.1	TSL:1	c.1352C>T	p.Ala451Val	missense	Exon 18 of 25	ENSP00000362419.1
	LRSAM1	ENST00000676170.1		c.1433C>T	p.Ala478Val	missense	Exon 20 of 27	ENSP00000502177.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152190 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000864

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

GnomAD2 exomes AF: 0.0000464 AC: 11 AN: 237226 AF XY: 0.0000625

Gnomad AFR exome AF: 0.0000669

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000618

Gnomad EAS exome AF: 0.0000566

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000261 AC: 38 AN: 1454796 Hom.: 0 Cov.: 32 AF XY: 0.0000304 AC XY: 22 AN XY: 722860

African (AFR) AF: 0.0000598 AC: 2 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 43620

Ashkenazi Jewish (ASJ) AF: 0.000618 AC: 16 AN: 25902

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39510

South Asian (SAS) AF: 0.0000474 AC: 4 AN: 84358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109534

Other (OTH) AF: 0.0000664 AC: 4 AN: 60220

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152190 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

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

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Charcot-Marie-Tooth disease axonal type 2P (3)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.81
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.0
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.031
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.12		Loss of disorder (P = 0.069)
MVP		0.75
MPC		0.17
ClinPred		0.043	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.083
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: rs751593173; hg19: chr9-130251727; COSMIC: COSV100031422; COSMIC: COSV100031422;