NM_005592.4:c.1189T>A

Variant names:

• chr9-110775792-T-A
• rs79843573
• NM_005592.4:c.1189T>A

Variant summary

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

The NM_005592.4(MUSK):​c.1189T>A​(p.Tyr397Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y397H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MUSK NM_005592.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.34
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 9

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC107987115 (HGNC:):

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=0.39807266).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005592.4. 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
	MUSK	NM_005592.4	MANE Select	c.1189T>A	p.Tyr397Asn	missense	Exon 10 of 15	NP_005583.1	O15146-1
	MUSK	NM_001166280.2		c.955T>A	p.Tyr319Asn	missense	Exon 10 of 14	NP_001159752.1	O15146-2
	MUSK	NM_001166281.2		c.925T>A	p.Tyr309Asn	missense	Exon 9 of 13	NP_001159753.1	O15146-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUSK	ENST00000374448.9	TSL:5 MANE Select	c.1189T>A	p.Tyr397Asn	missense	Exon 10 of 15	ENSP00000363571.4	O15146-1
	MUSK	ENST00000416899.7	TSL:5	c.1189T>A	p.Tyr397Asn	missense	Exon 10 of 14	ENSP00000393608.3	A0A087WSY1
	MUSK	ENST00000189978.10	TSL:5	c.955T>A	p.Tyr319Asn	missense	Exon 10 of 14	ENSP00000189978.6	O15146-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.069	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.3
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.56	N
REVEL	Uncertain	0.33
Sift	Benign	0.67	T
Sift4G	Benign	0.30	T
Polyphen		0.78	P
Vest4		0.11
MutPred		0.62		Loss of methylation at K402 (P = 0.0473)
MVP		0.80
MPC		0.49
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.085
gMVP		0.79
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs79843573; hg19: chr9-113538072;