rs373990000

Variant names:

• chr9-127502866-C-T
• rs373990000
• NM_001005373.4:c.2139C>T
• LRSAM1 p.Ile713Ile

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001005373.4(LRSAM1):​c.2139C>T​(p.Ile713Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,609,486 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: LRSAM1 NM_001005373.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.403
• 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: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 9-127502866-C-T is Benign according to our data. Variant chr9-127502866-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 540015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.403 with no splicing effect.

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.2139C>T	p.Ile713Ile	synonymous	Exon 26 of 26	NP_001005373.1	Q6UWE0-1
	LRSAM1	NM_001005374.4		c.2139C>T	p.Ile713Ile	synonymous	Exon 25 of 25	NP_001005374.1	Q6UWE0-1
	LRSAM1	NM_001384142.1		c.2139C>T	p.Ile713Ile	synonymous	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.2139C>T	p.Ile713Ile	synonymous	Exon 26 of 26	ENSP00000300417.6	Q6UWE0-1
	LRSAM1	ENST00000373322.1	TSL:1	c.2139C>T	p.Ile713Ile	synonymous	Exon 25 of 25	ENSP00000362419.1	Q6UWE0-1
	LRSAM1	ENST00000870574.1		c.2295C>T	p.Ile765Ile	synonymous	Exon 26 of 26	ENSP00000540633.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152196 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000163 AC: 39 AN: 239750 AF XY: 0.000153

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000227

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000288

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 337 AN: 1457172 Hom.: 0 Cov.: 34 AF XY: 0.000207 AC XY: 150 AN XY: 724666

African (AFR) AF: 0.0000599 AC: 2 AN: 33400

American (AMR) AF: 0.0000226 AC: 1 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26020

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39500

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85598

European-Finnish (FIN) AF: 0.0000383 AC: 2 AN: 52236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.000287 AC: 319 AN: 1110538

Other (OTH) AF: 0.000116 AC: 7 AN: 60174

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152314 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74482

African (AFR) AF: 0.0000722 AC: 3 AN: 41574

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

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

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.000147

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Charcot-Marie-Tooth disease axonal type 2P (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	LRSAM1-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.7
DANN	Benign	0.85
PhyloP100		0.40
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373990000;

hg19: chr9-130265145;