1-1049791-C-T

Position:

• chr1-1049791-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198576.4(AGRN):​c.4740C>T​(p.Arg1580Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,595,942 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (63 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (67 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.224

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-1049791-C-T is Benign according to our data. Variant chr1-1049791-C-T is described in ClinVar as [Benign]. Clinvar id is 128311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.224 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.4740C>T	p.Arg1580Arg	synonymous_variant	26/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.4740C>T	p.Arg1580Arg	synonymous_variant	26/36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1	c.4425C>T	p.Arg1475Arg	synonymous_variant	25/38			ENSP00000499046.1
AGRN	ENST00000652369.1	c.4425C>T	p.Arg1475Arg	synonymous_variant	25/35			ENSP00000498543.1
AGRN	ENST00000620552.4	c.4326C>T	p.Arg1442Arg	synonymous_variant	26/39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2463 AN: 151724 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0566

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00564

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00392 AC: 835 AN: 212948 Hom.: 21 AF XY: 0.00311 AC XY: 368 AN XY: 118160

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.00248

Gnomad ASJ exome AF: 0.000224

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000173

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00174 AC: 2510 AN: 1444100 Hom.: 67 Cov.: 44 AF XY: 0.00150 AC XY: 1073 AN XY: 716942

Gnomad4 AFR exome AF: 0.0617

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.000195

Gnomad4 EAS exome AF: 0.0000769

Gnomad4 SAS exome AF: 0.000130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000897

Gnomad4 OTH exome AF: 0.00368

GnomAD4 genome AF: 0.0162 AC: 2462 AN: 151842 Hom.: 63 Cov.: 32 AF XY: 0.0161 AC XY: 1193 AN XY: 74260

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.00563

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.000679 Hom.: 2

Bravo AF: 0.0185

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 24, 2017	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2017	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. -

Congenital myasthenic syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.7
DANN	Benign	0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs115019873; hg19: chr1-985171;