Genetic Variant AGRN:p.Arg4Leu (chr1-1020183-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198576.4(AGRN):c.11G>T(p.Arg4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. R4P) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.41

Publications

0 publications found

Variant links:

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

AGRN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09358701).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.11G>T	p.Arg4Leu	missense	Exon 1 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.11G>T	p.Arg4Leu	missense	Exon 1 of 39	NP_001292204.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
AGRN	ENST00000379370.7	TSL:1 MANE Select	c.11G>T	p.Arg4Leu	missense	Exon 1 of 36	ENSP00000368678.2
AGRN	ENST00000620552.4	TSL:5	c.-404G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 39	ENSP00000484607.1
AGRN	ENST00000620552.4	TSL:5	c.-404G>T		5_prime_UTR	Exon 1 of 39	ENSP00000484607.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1182526

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

578112

African (AFR)

AF:

0.00

AC:

AN:

23364

American (AMR)

AF:

0.00

AC:

AN:

12742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16880

East Asian (EAS)

AF:

0.00

AC:

AN:

25420

South Asian (SAS)

AF:

0.00

AC:

AN:

47866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

978094

Other (OTH)

AF:

0.00

AC:

AN:

47488

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.42

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.36

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.2

PhyloP100

-1.4

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.62

REVEL

Benign

0.15

Sift

Benign

0.20

Sift4G

Benign

0.20

Vest4

0.062

MutPred

0.26

Loss of methylation at R4 (P = 0.0105)

MVP

0.51

MPC

0.54

ClinPred

0.080

GERP RS

-2.3

PromoterAI

0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

gMVP

0.34

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over