9-110695418-G-T

Position:

chr9-110695418-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_005592.4(MUSK):c.374G>T(p.Arg125Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000383 in 1,514,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

MUSK
NM_005592.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 6.91

Variant links:

Genes affected

MUSK (HGNC:7525): (muscle associated receptor tyrosine kinase) This gene encodes a muscle-specific tyrosine kinase receptor. The encoded protein may play a role in clustering of the acetylcholine receptor in the postsynaptic neuromuscular junction. Mutations in this gene have been associated with congenital myasthenic syndrome. Alternatively spliced transcript variants have been described.[provided by RefSeq, Oct 2009]

MUSK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-110695418-G-T is Pathogenic according to our data. Variant chr9-110695418-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211541.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MUSK	NM_005592.4 linkuse as main transcript	c.374G>T	p.Arg125Leu	missense_variant	4/15	ENST00000374448.9	NP_005583.1	O15146-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MUSK	ENST00000374448.9 linkuse as main transcript	c.374G>T	p.Arg125Leu	missense_variant	4/15	5	NM_005592.4	ENSP00000363571.4	O15146-1
MUSK	ENST00000416899.7 linkuse as main transcript	c.374G>T	p.Arg125Leu	missense_variant	4/14	5		ENSP00000393608.3	A0A087WSY1
MUSK	ENST00000189978.10 linkuse as main transcript	c.374G>T	p.Arg125Leu	missense_variant	4/14	5		ENSP00000189978.6	O15146-2
MUSK	ENST00000374439.1 linkuse as main transcript	c.68G>T	p.Arg23Leu	missense_variant	2/4	5		ENSP00000363562.2	F6XAJ2

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000488

AC:

AN:

163840

Hom.:

AF XY:

0.0000461

AC XY:

AN XY:

86724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000168

Gnomad NFE exome

AF:

0.0000724

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000352

AC:

AN:

1362074

Hom.:

Cov.:

AF XY:

0.0000267

AC XY:

AN XY:

673552

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000239

Gnomad4 NFE exome

AF:

0.0000295

Gnomad4 OTH exome

AF:

0.0000877

GnomAD4 genome

AF:

0.0000658

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000251

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000505

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25537362) -

Congenital myasthenic syndrome 4C

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 26, 2015

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.374G>T (p.R125L) alteration is located in exon 4 (coding exon 4) of the MUSK gene. This alteration results from a G to T substitution at nucleotide position 374, causing the arginine (R) at amino acid position 125 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2022

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 125 of the MUSK protein (p.Arg125Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with MUSK-related conditions. ClinVar contains an entry for this variant (Variation ID: 211541). 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 MUSK protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Uncertain

0.086

MetaRNN

Uncertain

0.44

T;T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.21

N;.;N;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.5

N;N;D;.;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.0040

D;D;D;.;.

Sift4G

Benign

0.82

T;T;T;T;T

Polyphen

1.0

D;.;.;.;.

Vest4

0.73

MVP

0.76

MPC

0.77

ClinPred

0.51

GERP RS

6.0

Varity_R

0.35

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over