9-127451659-A-G

Variant names:

• chr9-127451659-A-G
• rs760403428
• NM_001005373.4:c.-199A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001005373.4(LRSAM1):​c.-199A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 389,272 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: LRSAM1 NM_001005373.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.262
• 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: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 9-127451659-A-G is Benign according to our data. Variant chr9-127451659-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 365003.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRSAM1	NM_001005373.4	c.-199A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 26	ENST00000300417.11	NP_001005373.1
LRSAM1	NM_001005373.4	c.-199A>G		5_prime_UTR_variant	Exon 1 of 26	ENST00000300417.11	NP_001005373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRSAM1	ENST00000300417.11	c.-199A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 26	1	NM_001005373.4	ENSP00000300417.6
LRSAM1	ENST00000300417.11	c.-199A>G		5_prime_UTR_variant	Exon 1 of 26	1	NM_001005373.4	ENSP00000300417.6

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 151728 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000339

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000269 AC: 64 AN: 237544 Hom.: 0 Cov.: 0 AF XY: 0.000281 AC XY: 35 AN XY: 124642

African (AFR) AF: 0.00 AC: 0 AN: 8100

American (AMR) AF: 0.00 AC: 0 AN: 11570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7634

East Asian (EAS) AF: 0.00 AC: 0 AN: 17060

South Asian (SAS) AF: 0.00 AC: 0 AN: 24496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1014

European-Non Finnish (NFE) AF: 0.000407 AC: 57 AN: 140148

Other (OTH) AF: 0.000500 AC: 7 AN: 14004

GnomAD4 genome AF: 0.000171 AC: 26 AN: 151728 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74086

African (AFR) AF: 0.0000727 AC: 3 AN: 41284

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10548

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

European-Non Finnish (NFE) AF: 0.000339 AC: 23 AN: 67910

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000343 Hom.: 0

Bravo AF: 0.000238

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Jun 19, 2015

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.1
DANN	Benign	0.71
PhyloP100		-0.26
PromoterAI		0.0085	Neutral
Mutation Taster		=300/0	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

Other links and lift over

dbSNP: rs760403428; hg19: chr9-130213938;