rs1553176512

Positions:

Variant summary

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

The ENST00000379370.7(AGRN):​c.3046A>G​(p.Thr1016Ala) 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

AGRN
ENST00000379370.7 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.653
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 -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.042013377).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGRNNM_198576.4 linkuse as main transcriptc.3046A>G p.Thr1016Ala missense_variant 18/36 ENST00000379370.7 NP_940978.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGRNENST00000379370.7 linkuse as main transcriptc.3046A>G p.Thr1016Ala missense_variant 18/361 NM_198576.4 ENSP00000368678 P1O00468-6
AGRNENST00000651234.1 linkuse as main transcriptc.2731A>G p.Thr911Ala missense_variant 17/38 ENSP00000499046
AGRNENST00000652369.1 linkuse as main transcriptc.2731A>G p.Thr911Ala missense_variant 17/35 ENSP00000498543
AGRNENST00000620552.4 linkuse as main transcriptc.2632A>G p.Thr878Ala missense_variant 18/395 ENSP00000484607

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
54
GnomAD4 genome
Cov.:
33

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), LabcorpAug 16, 2019In summary, this variant has uncertain impact on AGRN function. The available evidence is currently insufficient to determine its role 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a AGRN-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 1016 of the AGRN protein (p.Thr1016Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
0.13
DANN
Benign
0.31
Eigen
Benign
-2.1
Eigen_PC
Benign
-2.1
FATHMM_MKL
Benign
0.065
N
LIST_S2
Benign
0.33
T;T
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.042
T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
-0.34
N;.
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.28
N;.
REVEL
Benign
0.099
Sift
Benign
0.94
T;.
Sift4G
Benign
0.43
T;T
Vest4
0.072
MutPred
0.21
Loss of glycosylation at T1016 (P = 8e-04);.;
MVP
0.55
MPC
0.12
ClinPred
0.023
T
GERP RS
-8.3
gMVP
0.21

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1553176512; hg19: chr1-981911; API