rs750933418

chr1-1020344-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198576.4(AGRN):c.172G>A(p.Asp58Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000369 in 1,494,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.46

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 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=0.1935907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.172G>A	p.Asp58Asn	missense_variant	1/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.172G>A	p.Asp58Asn	missense_variant	1/36	1	NM_198576.4	P1
AGRN	ENST00000620552.4	c.-243G>A		5_prime_UTR_variant	1/39	5

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 151846 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

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: 0.000545

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000226 AC: 23 AN: 101738 Hom.: 0 AF XY: 0.000160 AC XY: 9 AN XY: 56128

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000522

Gnomad ASJ exome AF: 0.000428

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000560

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000381 AC: 512 AN: 1342722 Hom.: 0 Cov.: 32 AF XY: 0.000400 AC XY: 265 AN XY: 662312

Gnomad4 AFR exome AF: 0.0000369

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000553

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000459

Gnomad4 OTH exome AF: 0.000272

GnomAD4 genome AF: 0.000263 AC: 40 AN: 151954 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74294

Gnomad4 AFR AF: 0.0000722

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: 0.000545

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000420 Hom.: 0

Bravo AF: 0.000268

ExAC AF: 0.000154 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Congenital myasthenic syndrome 8 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 58 of the AGRN protein (p.Asp58Asn). This variant is present in population databases (rs750933418, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with AGRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 571135). 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: "Not Available"; Align-GVGD: "Class C0"). In 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 19, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.50
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.95	N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Vest4		0.34
MutPred		0.74		Gain of MoRF binding (P = 0.0662);
MVP		0.63
MPC		0.42
ClinPred		0.23	T
GERP RS		1.3
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs750933418; hg19: chr1-955724;