rs375737188

chr9-110695418-G-Achr9-110695418-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_005592.4(MUSK):c.374G>A(p.Arg125His) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,514,038 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000046 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2501967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUSK	NM_005592.4	c.374G>A	p.Arg125His	missense_variant	4/15	ENST00000374448.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUSK	ENST00000374448.9	c.374G>A	p.Arg125His	missense_variant	4/15	5	NM_005592.4	P4
MUSK	ENST00000416899.7	c.374G>A	p.Arg125His	missense_variant	4/14	5		A1
MUSK	ENST00000189978.10	c.374G>A	p.Arg125His	missense_variant	4/14	5
MUSK	ENST00000374439.1	c.68G>A	p.Arg23His	missense_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151964 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000854 AC: 14 AN: 163840 Hom.: 0 AF XY: 0.0000461 AC XY: 4 AN XY: 86724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000896

Gnomad ASJ exome AF: 0.000718

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000434

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.0000492 AC: 67 AN: 1362074 Hom.: 0 Cov.: 26 AF XY: 0.0000445 AC XY: 30 AN XY: 673552

Gnomad4 AFR exome AF: 0.0000323

Gnomad4 AMR exome AF: 0.0000593

Gnomad4 ASJ exome AF: 0.000526

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000817

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000381

Gnomad4 OTH exome AF: 0.0000526

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151964 Hom.: 1 Cov.: 33 AF XY: 0.0000674 AC XY: 5 AN XY: 74208

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000501 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000253 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2023

The c.374G>A (p.R125H) alteration is located in exon 4 (coding exon 4) of the MUSK gene. This alteration results from a G to A substitution at nucleotide position 374, causing the arginine (R) at amino acid position 125 to be replaced by a histidine (H). 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

Invitae

Aug 24, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 125 of the MUSK protein (p.Arg125His). 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: 542747). 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 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. -

Congenital myasthenic syndrome 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.15	T;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.6	L;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.7	N;N;N;.;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;D;D;.;.
Sift4G	Benign	0.097	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.60
MVP		0.78
MPC		0.77
ClinPred		0.29	T
GERP RS		6.0
Varity_R		0.37
gMVP		0.64

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: rs375737188; hg19: chr9-113457698; COSMIC: COSV51885774;