rs759844691

Variant names:

• chr1-1043303-C-A
• rs759844691
• NM_198576.4:c.1449C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-1043303-C-A
• chr1-1043303-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198576.4(AGRN):​c.1449C>A​(p.Asn483Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. N483D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.227
• Publications: 0 publications found

Genes affected

AGRN (HGNC:329): (agrin) This gene encodes one of several proteins that are critical in the development of the neuromuscular junction (NMJ), as identified in mouse knock-out studies. The encoded protein contains several laminin G, Kazal type serine protease inhibitor, and epidermal growth factor domains. Additional post-translational modifications occur to add glycosaminoglycans and disulfide bonds. In one family with congenital myasthenic syndrome affecting limb-girdle muscles, a mutation in this gene was found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

AGRN Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. 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
	AGRN	NM_198576.4	MANE Select	c.1449C>A	p.Asn483Lys	missense	Exon 8 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.1449C>A	p.Asn483Lys	missense	Exon 8 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.1134C>A	p.Asn378Lys	missense	Exon 7 of 36	NP_001351656.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.1449C>A	p.Asn483Lys	missense	Exon 8 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.1134C>A	p.Asn378Lys	missense	Exon 7 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.1134C>A	p.Asn378Lys	missense	Exon 7 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459296 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725822

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000225 AC: 1 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111498

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	3.6
DANN	Benign	0.95
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.23
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.40
Sift	Benign	0.041	D
Sift4G	Uncertain	0.045	D
Vest4		0.67
MutPred		0.73		Gain of ubiquitination at N483 (P = 0.0211)
MVP		0.61
MPC		0.36
ClinPred		0.91	D
GERP RS		-9.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.46
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs759844691; hg19: chr1-978683;