NM_001005373.4:c.-33+51C>T

Variant names:

• chr9-127452135-C-T
• rs3808831
• NM_001005373.4:c.-33+51C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001005373.4(LRSAM1):​c.-33+51C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,300 control chromosomes in the GnomAD database, including 1,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1342 hom., cov: 32)
  • Exomes 𝑓: 0.034 (0 hom.)
• Consequence: LRSAM1 NM_001005373.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.31
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-127452135-C-T is Benign according to our data. Variant chr9-127452135-C-T is described in ClinVar as [Benign]. Clinvar id is 674025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRSAM1	NM_001005373.4	c.-33+51C>T		intron_variant	Intron 2 of 25	ENST00000300417.11	NP_001005373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRSAM1	ENST00000300417.11	c.-33+51C>T		intron_variant	Intron 2 of 25	1	NM_001005373.4	ENSP00000300417.6

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15952 AN: 152124 Hom.: 1333 Cov.: 32

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.0938

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0974

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.0345 AC: 2 AN: 58 Hom.: 0 Cov.: 0 AF XY: 0.0227 AC XY: 1 AN XY: 44

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.0833 AC: 1 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0250 AC: 1 AN: 40

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.105 AC: 15973 AN: 152242 Hom.: 1342 Cov.: 32 AF XY: 0.109 AC XY: 8139 AN XY: 74436

African (AFR) AF: 0.0375 AC: 1558 AN: 41572

American (AMR) AF: 0.274 AC: 4196 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3472

East Asian (EAS) AF: 0.205 AC: 1056 AN: 5158

South Asian (SAS) AF: 0.147 AC: 708 AN: 4820

European-Finnish (FIN) AF: 0.0938 AC: 996 AN: 10616

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0974 AC: 6624 AN: 67992

Other (OTH) AF: 0.123 AC: 259 AN: 2114

Alfa AF: 0.0497 Hom.: 50

Bravo AF: 0.122

Asia WGS AF: 0.149 AC: 518 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 20, 2018

GeneDx

Significance: 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	-0.86
CADD	Benign	6.2
DANN	Benign	0.82
PhyloP100		-3.3
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs3808831; hg19: chr9-130214414;