chr9-127454591-A-T

Variant names:

• chr9-127454591-A-T
• rs769236666
• NM_001005373.4:c.64A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001384144.1(LRSAM1):​c.-721A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRSAM1 NM_001384144.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16
• 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: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2758694).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384144.1. 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.64A>T	p.Met22Leu	missense	Exon 3 of 26	NP_001005373.1	Q6UWE0-1
	LRSAM1	NM_001384144.1		c.-721A>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 26	NP_001371073.1
	LRSAM1	NM_001005374.4		c.64A>T	p.Met22Leu	missense	Exon 2 of 25	NP_001005374.1	Q6UWE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRSAM1	ENST00000300417.11	TSL:1 MANE Select	c.64A>T	p.Met22Leu	missense	Exon 3 of 26	ENSP00000300417.6	Q6UWE0-1
	LRSAM1	ENST00000373322.1	TSL:1	c.64A>T	p.Met22Leu	missense	Exon 2 of 25	ENSP00000362419.1	Q6UWE0-1
	LRSAM1	ENST00000870574.1		c.64A>T	p.Met22Leu	missense	Exon 3 of 26	ENSP00000540633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250970 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461588 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727102

African (AFR) AF: 0.0000299 AC: 1 AN: 33428

American (AMR) AF: 0.0000224 AC: 1 AN: 44710

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111910

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.043	T
Eigen	Benign	0.055
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.090	N
PhyloP100		3.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.19
Sift	Benign	0.72	T
Sift4G	Benign	0.51	T
Polyphen		0.73	P
Vest4		0.39
MutPred		0.48		Loss of catalytic residue at M22 (P = 0.0057)
MVP		0.43
MPC		0.16
ClinPred		0.30	T
GERP RS		5.3
Varity_R		0.29
gMVP		0.32
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs769236666; hg19: chr9-130216870;