1-1050763-G-T

Variant names:

• chr1-1050763-G-T
• rs587777298
• NM_198576.4:c.5179G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM2 PP3_Strong PP5_Moderate

The NM_198576.4(AGRN):​c.5179G>T​(p.Val1727Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV003284619: Experimental studies have shown that this missense change affects AGRN function (PMID:22205389, 30994901).". Synonymous variant affecting the same amino acid position (i.e. V1727V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 3.93
• Publications: 16 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: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003284619: Experimental studies have shown that this missense change affects AGRN function (PMID: 22205389, 30994901).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 1-1050763-G-T is Pathogenic according to our data. Variant chr1-1050763-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 126555.Status of the report is criteria_provided_single_submitter, 1 stars.

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.5179G>T	p.Val1727Phe	missense	Exon 30 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.5179G>T	p.Val1727Phe	missense	Exon 30 of 39	NP_001292204.1	O00468-1
	AGRN	NM_001364727.2		c.4864G>T	p.Val1622Phe	missense	Exon 29 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.5179G>T	p.Val1727Phe	missense	Exon 30 of 36	ENSP00000368678.2	O00468-6
	AGRN	ENST00000651234.1		c.4864G>T	p.Val1622Phe	missense	Exon 29 of 38	ENSP00000499046.1	A0A494C1I6
	AGRN	ENST00000652369.2		c.4864G>T	p.Val1622Phe	missense	Exon 29 of 35	ENSP00000498543.1	A0A494C0G5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451708 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 721960

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39460

South Asian (SAS) AF: 0.00 AC: 0 AN: 85362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4320

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109938

Other (OTH) AF: 0.00 AC: 0 AN: 59926

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Congenital myasthenic syndrome 8 (2)
-	-	-	Congenital myasthenic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		3.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.91
MutPred		0.66		Loss of catalytic residue at V1727 (P = 0.0849)
MVP		0.92
MPC		0.66
ClinPred		0.97	D
GERP RS		4.4
gMVP		0.93
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs587777298; hg19: chr1-986143;