rs149159118

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_198576.4(AGRN):​c.3353C>A​(p.Thr1118Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,579,524 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1118M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0020 ( 1 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

1
12
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.50
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.012785703).
BP6
Variant 1-1046922-C-A is Benign according to our data. Variant chr1-1046922-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474116.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr1-1046922-C-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AGRNNM_198576.4 linkuse as main transcriptc.3353C>A p.Thr1118Lys missense_variant 19/36 ENST00000379370.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AGRNENST00000379370.7 linkuse as main transcriptc.3353C>A p.Thr1118Lys missense_variant 19/361 NM_198576.4 P1O00468-6
AGRNENST00000651234.1 linkuse as main transcriptc.3038C>A p.Thr1013Lys missense_variant 18/38
AGRNENST00000652369.1 linkuse as main transcriptc.3038C>A p.Thr1013Lys missense_variant 18/35
AGRNENST00000620552.4 linkuse as main transcriptc.2939C>A p.Thr980Lys missense_variant 19/395

Frequencies

GnomAD3 genomes
AF:
0.00183
AC:
279
AN:
152172
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0107
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00203
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.00187
AC:
356
AN:
190804
Hom.:
0
AF XY:
0.00190
AC XY:
194
AN XY:
102348
show subpopulations
Gnomad AFR exome
AF:
0.000435
Gnomad AMR exome
AF:
0.000690
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000400
Gnomad FIN exome
AF:
0.00868
Gnomad NFE exome
AF:
0.00211
Gnomad OTH exome
AF:
0.000800
GnomAD4 exome
AF:
0.00198
AC:
2824
AN:
1427234
Hom.:
1
Cov.:
39
AF XY:
0.00192
AC XY:
1354
AN XY:
706762
show subpopulations
Gnomad4 AFR exome
AF:
0.000303
Gnomad4 AMR exome
AF:
0.000619
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000466
Gnomad4 FIN exome
AF:
0.00732
Gnomad4 NFE exome
AF:
0.00210
Gnomad4 OTH exome
AF:
0.00142
GnomAD4 genome
AF:
0.00183
AC:
279
AN:
152290
Hom.:
1
Cov.:
33
AF XY:
0.00228
AC XY:
170
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.000361
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0107
Gnomad4 NFE
AF:
0.00203
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00152
Hom.:
0
Bravo
AF:
0.00100
TwinsUK
AF:
0.00189
AC:
7
ALSPAC
AF:
0.00234
AC:
9
ESP6500AA
AF:
0.000229
AC:
1
ESP6500EA
AF:
0.00163
AC:
14
ExAC
AF:
0.00117
AC:
140

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 09, 2021In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24951643, 26290588) -
Congenital myasthenic syndrome 8 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
24
DANN
Uncertain
0.99
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D
MetaRNN
Benign
0.013
T;T
MetaSVM
Uncertain
0.16
D
MutationAssessor
Uncertain
2.6
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-2.6
D;.
REVEL
Uncertain
0.45
Sift
Uncertain
0.0040
D;.
Sift4G
Uncertain
0.0030
D;D
Vest4
0.74
MVP
0.89
MPC
0.63
ClinPred
0.024
T
GERP RS
4.2
RBP_binding_hub_radar
1.0
RBP_regulation_power_radar
2.1
gMVP
0.86

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: rs149159118; hg19: chr1-982302; API