rs76264143

chr1-1047464-G-C

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.3516+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,612,648 control chromosomes in the GnomAD database, including 3,950 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (281 hom., cov: 34)
  • Exomes 𝑓: 0.068 (3669 hom.)
• Consequence: AGRN NM_198576.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.388

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 (BayesDel_noAF=-0.9).
• BP6: Variant 1-1047464-G-C is Benign according to our data. Variant chr1-1047464-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 128301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.3516+10G>C		intron_variant		ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.3516+10G>C		intron_variant		1	NM_198576.4	P1

Frequencies

GnomAD3 genomes AF: 0.0514 AC: 7827 AN: 152206 Hom.: 281 Cov.: 34

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0497

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0782

Gnomad FIN AF: 0.0521

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0751

Gnomad OTH AF: 0.0559

GnomAD3 exomes AF: 0.0581 AC: 14445 AN: 248474 Hom.: 567 AF XY: 0.0618 AC XY: 8349 AN XY: 135142

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.0337

Gnomad ASJ exome AF: 0.0946

Gnomad EAS exome AF: 0.000273

Gnomad SAS exome AF: 0.0782

Gnomad FIN exome AF: 0.0532

Gnomad NFE exome AF: 0.0736

Gnomad OTH exome AF: 0.0650

GnomAD4 exome AF: 0.0679 AC: 99140 AN: 1460324 Hom.: 3669 Cov.: 33 AF XY: 0.0690 AC XY: 50105 AN XY: 726456

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.0348

Gnomad4 ASJ exome AF: 0.0956

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0796

Gnomad4 FIN exome AF: 0.0526

Gnomad4 NFE exome AF: 0.0727

Gnomad4 OTH exome AF: 0.0620

GnomAD4 genome AF: 0.0513 AC: 7819 AN: 152324 Hom.: 281 Cov.: 34 AF XY: 0.0505 AC XY: 3761 AN XY: 74470

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.0496

Gnomad4 ASJ AF: 0.0956

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0783

Gnomad4 FIN AF: 0.0521

Gnomad4 NFE AF: 0.0750

Gnomad4 OTH AF: 0.0549

Alfa AF: 0.0677 Hom.: 91

Bravo AF: 0.0482

Asia WGS AF: 0.0280 AC: 101 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	research	Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	Sep 28, 2016	- -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.0
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs76264143; hg19: chr1-982844;