rs1553176512

Positions:

• chr1-1046531-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.653

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]

ACMG classification

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
AGRN	NM_198576.4	c.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
AGRN	ENST00000379370.7	c.3046A>G	p.Thr1016Ala	missense_variant	18/36	1	NM_198576.4	ENSP00000368678	P1
AGRN	ENST00000651234.1	c.2731A>G	p.Thr911Ala	missense_variant	17/38			ENSP00000499046
AGRN	ENST00000652369.1	c.2731A>G	p.Thr911Ala	missense_variant	17/35			ENSP00000498543
AGRN	ENST00000620552.4	c.2632A>G	p.Thr878Ala	missense_variant	18/39	5		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

Submissions by phenotype

Congenital myasthenic syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2019

In 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

Other links and lift over

dbSNP: rs1553176512; hg19: chr1-981911;