9-127489524-C-T

Variant names:

• chr9-127489524-C-T
• rs745690669
• NM_001005373.4:c.1422+6C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001005373.4(LRSAM1):​c.1422+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000555 in 1,604,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: LRSAM1 NM_001005373.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002852
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.760

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRSAM1	NM_001005373.4	c.1422+6C>T		splice_region_variant, intron_variant	Intron 19 of 25	ENST00000300417.11	NP_001005373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRSAM1	ENST00000300417.11	c.1422+6C>T		splice_region_variant, intron_variant	Intron 19 of 25	1	NM_001005373.4	ENSP00000300417.6

Frequencies

GnomAD3 genomes AF: 0.0000594 AC: 9 AN: 151444 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

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: 0.000103

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.000117 AC: 27 AN: 231196 Hom.: 0 AF XY: 0.000120 AC XY: 15 AN XY: 124894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000308

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000355

Gnomad FIN exome AF: 0.0000518

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000550 AC: 80 AN: 1453408 Hom.: 0 Cov.: 32 AF XY: 0.0000568 AC XY: 41 AN XY: 722086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.000134

Gnomad4 NFE exome AF: 0.0000523

Gnomad4 OTH exome AF: 0.000216

GnomAD4 genome AF: 0.0000594 AC: 9 AN: 151444 Hom.: 0 Cov.: 34 AF XY: 0.0000947 AC XY: 7 AN XY: 73936

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000665

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000482

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Unlikely to be causative of LRSAM1-related Charcot-Marie-Tooth disease, type 2 (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2P Uncertain:1

Dec 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 18 of the LRSAM1 gene. It does not directly change the encoded amino acid sequence of the LRSAM1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs745690669, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LRSAM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 472791). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.24
DANN	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs745690669; hg19: chr9-130251803;