1-1041583-A-G

Position:

• chr1-1041583-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):​c.1058A>G​(p.Gln353Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,606,080 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (47 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (55 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.90

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021865368).
• BP6: Variant 1-1041583-A-G is Benign according to our data. Variant chr1-1041583-A-G is described in ClinVar as [Benign]. Clinvar id is 128291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.1058A>G	p.Gln353Arg	missense_variant	6/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.1058A>G	p.Gln353Arg	missense_variant	6/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.743A>G	p.Gln248Arg	missense_variant	5/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.743A>G	p.Gln248Arg	missense_variant	5/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.644A>G	p.Gln215Arg	missense_variant	6/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2343 AN: 151214 Hom.: 47 Cov.: 31

Gnomad AFR AF: 0.0540

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00427

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.00914

GnomAD3 exomes AF: 0.00386 AC: 916 AN: 237174 Hom.: 21 AF XY: 0.00294 AC XY: 385 AN XY: 130756

Gnomad AFR exome AF: 0.0539

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.00174 AC: 2529 AN: 1454750 Hom.: 55 Cov.: 33 AF XY: 0.00150 AC XY: 1089 AN XY: 723978

Gnomad4 AFR exome AF: 0.0547

Gnomad4 AMR exome AF: 0.00294

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000884

Gnomad4 NFE exome AF: 0.000287

Gnomad4 OTH exome AF: 0.00332

GnomAD4 genome AF: 0.0155 AC: 2346 AN: 151330 Hom.: 47 Cov.: 31 AF XY: 0.0153 AC XY: 1133 AN XY: 73986

Gnomad4 AFR AF: 0.0539

Gnomad4 AMR AF: 0.00426

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00105

Gnomad4 NFE AF: 0.000354

Gnomad4 OTH AF: 0.00905

Alfa AF: 0.00236 Hom.: 4

Bravo AF: 0.0174

ESP6500AA AF: 0.0411 AC: 173

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.00457 AC: 547

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2019	- -

AGRN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0040
DANN	Benign	0.18
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.10	N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.050	N;.
REVEL	Benign	0.18
Sift	Benign	0.65	T;.
Sift4G	Benign	0.60	T;T
Vest4		0.056
MVP		0.55
MPC		0.63
ClinPred		0.0013	T
GERP RS		-9.3
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs150359724; hg19: chr1-976963;