rs375197922

Variant summary

Our verdict is Uncertain significance. Variant got 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. 16/21 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 (★). Synonymous variant affecting the same amino acid position (i.e. T1172T) 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
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18295929).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGRNNM_198576.4 linkc.3515C>A p.Thr1172Asn missense_variant, splice_region_variant 20/36 ENST00000379370.7 NP_940978.2 O00468-6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGRNENST00000379370.7 linkc.3515C>A p.Thr1172Asn missense_variant, splice_region_variant 20/361 NM_198576.4 ENSP00000368678.2 O00468-6

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
Gnomad4 AFR
AF:
0.0000482
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
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0

ClinVar

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

Submissions by phenotype

Congenital myasthenic syndrome 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 01, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 565843). This variant has not been reported in the literature in individuals affected with AGRN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1172 of the AGRN protein (p.Thr1172Asn). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
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;D
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.18
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.5
N;.
REVEL
Benign
0.048
Sift
Uncertain
0.028
D;.
Sift4G
Uncertain
0.0040
D;D
Vest4
0.26
MVP
0.59
MPC
0.52
ClinPred
0.39
T
GERP RS
2.2
gMVP
0.52

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

LitVar

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

Other links and lift over

dbSNP: rs375197922; hg19: chr1-982833; API