NM_198576.4:c.904G>A

Variant names:

• chr1-1041349-G-A
• rs1318084676
• NM_198576.4:c.904G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198576.4(AGRN):​c.904G>A​(p.Ala302Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000131 in 1,529,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A302G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.24
• 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: DEFINITIVE, STRONG Submitted by: ClinGen, 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.904G>A	p.Ala302Thr	missense	Exon 5 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.904G>A	p.Ala302Thr	missense	Exon 5 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.589G>A	p.Ala197Thr	missense	Exon 4 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.904G>A	p.Ala302Thr	missense	Exon 5 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.589G>A	p.Ala197Thr	missense	Exon 4 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.589G>A	p.Ala197Thr	missense	Exon 4 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151998 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1377006 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 679978

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31032

American (AMR) AF: 0.00 AC: 0 AN: 33870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24298

East Asian (EAS) AF: 0.00 AC: 0 AN: 35924

South Asian (SAS) AF: 0.00 AC: 0 AN: 78338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076798

Other (OTH) AF: 0.00 AC: 0 AN: 57408

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151998 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74236

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2088

ClinVar

ClinVar submissions

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	Uncertain	0.54
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.26
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.053	T
Vest4		0.42
MutPred		0.53		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.73
MPC		1.1
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
gMVP		0.63
Mutation Taster		=71/29	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: rs1318084676; hg19: chr1-976729; COSMIC: COSV65070872; COSMIC: COSV65070872;