chr1-1020204-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198576.4(AGRN):​c.32G>T​(p.Arg11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000512 in 1,368,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign 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. R11Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000025 ( 0 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.11
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.067261994).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AGRNNM_198576.4 linkuse as main transcriptc.32G>T p.Arg11Leu missense_variant 1/36 ENST00000379370.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AGRNENST00000379370.7 linkuse as main transcriptc.32G>T p.Arg11Leu missense_variant 1/361 NM_198576.4 P1O00468-6
AGRNENST00000620552.4 linkuse as main transcriptc.-383G>T 5_prime_UTR_variant 1/395

Frequencies

GnomAD3 genomes
AF:
0.0000265
AC:
4
AN:
151164
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000970
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000247
AC:
3
AN:
1216950
Hom.:
0
Cov.:
29
AF XY:
0.00000168
AC XY:
1
AN XY:
596600
show subpopulations
Gnomad4 AFR exome
AF:
0.000124
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000265
AC:
4
AN:
151164
Hom.:
0
Cov.:
31
AF XY:
0.0000271
AC XY:
2
AN XY:
73800
show subpopulations
Gnomad4 AFR
AF:
0.0000970
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 01, 2021The c.32G>T (p.R11L) alteration is located in exon 1 (coding exon 1) of the AGRN gene. This alteration results from a G to T substitution at nucleotide position 32, causing the arginine (R) at amino acid position 11 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
8.4
DANN
Benign
0.70
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.027
N
LIST_S2
Benign
0.39
T
M_CAP
Pathogenic
0.56
D
MetaRNN
Benign
0.067
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
-0.35
N
MutationTaster
Benign
1.0
N
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-0.14
N
REVEL
Benign
0.12
Sift
Benign
0.63
T
Sift4G
Benign
0.27
T
Vest4
0.18
MutPred
0.24
Loss of disorder (P = 0.0521);
MVP
0.52
MPC
0.54
ClinPred
0.037
T
GERP RS
-4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.4
gMVP
0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1281912578; hg19: chr1-955584; API