rs1554763017

Variant names:

• chr9-127502809-CTGCTGCCAGCAG-C
• rs1554763017
• NM_001005373.4:c.2093_2104delAGTGCTGCCAGC

Your query was ambiguous. Multiple possible variants found:

• chr9-127502809-CTGCTGCCAGCAG-C
• chr9-127502809-CTGCTGCCAGCAG-CTGCTGCCAGCAGTGCTGCCAGCAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM4 PP5_Very_Strong

The NM_001005373.4(LRSAM1):​c.2093_2104delAGTGCTGCCAGC​(p.Gln698_Gln701del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000186 in 1,611,934 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q698Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRSAM1 NM_001005373.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.10
• Publications: 1 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_001005373.4
• PM4: Nonframeshift variant in NON repetitive region in NM_001005373.4.
• PP5: Variant 9-127502809-CTGCTGCCAGCAG-C is Pathogenic according to our data. Variant chr9-127502809-CTGCTGCCAGCAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 472799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2093_2104delAGTGCTGCCAGC	p.Gln698_Gln701del	disruptive_inframe_deletion	Exon 26 of 26	NP_001005373.1	Q6UWE0-1
	LRSAM1	NM_001005374.4		c.2093_2104delAGTGCTGCCAGC	p.Gln698_Gln701del	disruptive_inframe_deletion	Exon 25 of 25	NP_001005374.1	Q6UWE0-1
	LRSAM1	NM_001384142.1		c.2093_2104delAGTGCTGCCAGC	p.Gln698_Gln701del	disruptive_inframe_deletion	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.2093_2104delAGTGCTGCCAGC	p.Gln698_Gln701del	disruptive_inframe_deletion	Exon 26 of 26	ENSP00000300417.6	Q6UWE0-1
	LRSAM1	ENST00000373322.1	TSL:1	c.2093_2104delAGTGCTGCCAGC	p.Gln698_Gln701del	disruptive_inframe_deletion	Exon 25 of 25	ENSP00000362419.1	Q6UWE0-1
	LRSAM1	ENST00000870574.1		c.2249_2260delAGTGCTGCCAGC	p.Gln750_Gln753del	disruptive_inframe_deletion	Exon 26 of 26	ENSP00000540633.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459786 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 726220

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111692

Other (OTH) AF: 0.00 AC: 0 AN: 60246

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2094

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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: rs1554763017;

hg19: chr9-130265088;