rs551423795
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP4
The NM_005592.4(MUSK):c.308A>G(p.Asn103Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N103N) has been classified as Likely benign.
Frequency
Consequence
NM_005592.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUSK | NM_005592.4 | c.308A>G | p.Asn103Ser | missense_variant | 3/15 | ENST00000374448.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUSK | ENST00000374448.9 | c.308A>G | p.Asn103Ser | missense_variant | 3/15 | 5 | NM_005592.4 | P4 | |
MUSK | ENST00000416899.7 | c.308A>G | p.Asn103Ser | missense_variant | 3/14 | 5 | A1 | ||
MUSK | ENST00000189978.10 | c.308A>G | p.Asn103Ser | missense_variant | 3/14 | 5 | |||
MUSK | ENST00000374439.1 | c.2A>G | p.Asn1Ser | missense_variant | 1/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152134Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000241 AC: 6AN: 249236Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135210
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461614Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727084
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152252Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74438
ClinVar
Submissions by phenotype
Fetal akinesia deformation sequence 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 16, 2017 | - - |
Fetal akinesia deformation sequence 1;C4225368:Congenital myasthenic syndrome 9 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 103 of the MUSK protein (p.Asn103Ser). This variant is present in population databases (rs551423795, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 25900532, 32253145). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218372). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Congenital myasthenic syndrome 9 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute | Dec 15, 2015 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 12, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at