rs375197922

Variant summary

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

The NM_198576.4(AGRN):​c.3515C>A​(p.Thr1172Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T1172A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Consequence

AGRN
NM_198576.4 missense, splice_region

Scores

3
14
Splicing: ADA: 0.0007215
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.87

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: 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

Genome browser will be placed here

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=0.18295929).

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.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
AGRN
NM_198576.4
MANE Select
c.3515C>Ap.Thr1172Asn
missense splice_region
Exon 20 of 36NP_940978.2
AGRN
NM_001305275.2
c.3515C>Ap.Thr1172Asn
missense splice_region
Exon 20 of 39NP_001292204.1O00468-1
AGRN
NM_001364727.2
c.3200C>Ap.Thr1067Asn
missense splice_region
Exon 19 of 36NP_001351656.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
AGRN
ENST00000379370.7
TSL:1 MANE Select
c.3515C>Ap.Thr1172Asn
missense splice_region
Exon 20 of 36ENSP00000368678.2O00468-6
AGRN
ENST00000651234.1
c.3200C>Ap.Thr1067Asn
missense splice_region
Exon 19 of 38ENSP00000499046.1A0A494C1I6
AGRN
ENST00000652369.2
c.3200C>Ap.Thr1067Asn
missense splice_region
Exon 19 of 35ENSP00000498543.1A0A494C0G5

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152238
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000482
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
Cov.:
32
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152238
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74374
show subpopulations
African (AFR)
AF:
0.0000482
AC:
2
AN:
41464
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5202
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0

ClinVar

ClinVar submissions
Significance:Uncertain significance
Revision:criteria provided, single submitter
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
1
-
Congenital myasthenic syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
12
DANN
Benign
0.78
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.95
D
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L
PhyloP100
2.9
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.5
N
REVEL
Benign
0.048
Sift
Uncertain
0.028
D
Sift4G
Uncertain
0.0040
D
Vest4
0.26
MVP
0.59
MPC
0.52
ClinPred
0.39
T
GERP RS
2.2
gMVP
0.52
Mutation Taster
=82/18
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00072
dbscSNV1_RF
Benign
0.16
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

Other links and lift over

dbSNP: rs375197922; hg19: chr1-982833; API
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.