rs150882646

Positions:

• chr9-127495982-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001005373.4(LRSAM1):​c.1717C>A​(p.Gln573Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,612,930 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: LRSAM1 NM_001005373.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.88

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.078140885).
• BP6: Variant 9-127495982-C-A is Benign according to our data. Variant chr9-127495982-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472795.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRSAM1	NM_001005373.4	c.1717C>A	p.Gln573Lys	missense_variant	23/26	ENST00000300417.11	NP_001005373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRSAM1	ENST00000300417.11	c.1717C>A	p.Gln573Lys	missense_variant	23/26	1	NM_001005373.4	ENSP00000300417	P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000176 AC: 44 AN: 249440 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135050

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000624

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1460582 Hom.: 2 Cov.: 32 AF XY: 0.000139 AC XY: 101 AN XY: 726578

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000523

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000782

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74480

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000109

EpiControl AF: 0.000237

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 05, 2023

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 573 of the LRSAM1 protein (p.Gln573Lys). This variant is present in population databases (rs150882646, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with LRSAM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 472795). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LRSAM1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2020

This variant is associated with the following publications: (PMID: 28335037) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T;.;T;T
Eigen	Benign	0.086
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D;D;.;.
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.078	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.1	M;.;M;M
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.090	B;B;B;B
Vest4		0.38
MVP		0.78
MPC		0.25
ClinPred		0.027	T
GERP RS		5.8
Varity_R		0.081
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs150882646; hg19: chr9-130258261;