9-127479385-A-G

Variant names:

• chr9-127479385-A-G
• rs1344070586
• NM_001005373.4:c.783A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The ENST00000300417.11(LRSAM1):​c.783A>G​(p.Glu261Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: LRSAM1 ENST00000300417.11 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.915
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 9-127479385-A-G is Benign according to our data. Variant chr9-127479385-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 540012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.915 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000300417.11. 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.783A>G	p.Glu261Glu	splice_region synonymous	Exon 13 of 26	NP_001005373.1
	LRSAM1	NM_001384144.1		c.-7A>G		splice_region	Exon 13 of 26	NP_001371073.1
	LRSAM1	NM_001005374.4		c.783A>G	p.Glu261Glu	splice_region synonymous	Exon 12 of 25	NP_001005374.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRSAM1	ENST00000300417.11	TSL:1 MANE Select	c.783A>G	p.Glu261Glu	splice_region synonymous	Exon 13 of 26	ENSP00000300417.6
	LRSAM1	ENST00000373322.1	TSL:1	c.783A>G	p.Glu261Glu	splice_region synonymous	Exon 12 of 25	ENSP00000362419.1
	LRSAM1	ENST00000676170.1		c.783A>G	p.Glu261Glu	splice_region synonymous	Exon 13 of 27	ENSP00000502177.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Benign	0.81
PhyloP100		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1344070586; hg19: chr9-130241664;