1-1047614-T-C

Position:

• chr1-1047614-T-C

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.3558T>C​(p.Phe1186Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.907 in 1,612,940 control chromosomes in the GnomAD database, including 669,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (53400 hom., cov: 35)
  • Exomes 𝑓: 0.92 (616018 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.15

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]

AGRN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-1047614-T-C is Benign according to our data. Variant chr1-1047614-T-C is described in ClinVar as [Benign]. Clinvar id is 128302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1047614-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4	c.3558T>C	p.Phe1186Phe	synonymous_variant	21/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.3558T>C	p.Phe1186Phe	synonymous_variant	21/36	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes AF: 0.820 AC: 124694 AN: 152140 Hom.: 53403 Cov.: 35

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.896

Gnomad ASJ AF: 0.924

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.957

Gnomad FIN AF: 0.958

Gnomad MID AF: 0.879

Gnomad NFE AF: 0.920

Gnomad OTH AF: 0.846

GnomAD3 exomes AF: 0.908 AC: 227622 AN: 250598 Hom.: 104766 AF XY: 0.916 AC XY: 124297 AN XY: 135754

Gnomad AFR exome AF: 0.525

Gnomad AMR exome AF: 0.939

Gnomad ASJ exome AF: 0.923

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.953

Gnomad FIN exome AF: 0.953

Gnomad NFE exome AF: 0.917

Gnomad OTH exome AF: 0.908

GnomAD4 exome AF: 0.916 AC: 1337920 AN: 1460682 Hom.: 616018 Cov.: 92 AF XY: 0.918 AC XY: 667056 AN XY: 726632

Gnomad4 AFR exome AF: 0.516

Gnomad4 AMR exome AF: 0.933

Gnomad4 ASJ exome AF: 0.920

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.952

Gnomad4 FIN exome AF: 0.951

Gnomad4 NFE exome AF: 0.921

Gnomad4 OTH exome AF: 0.901

GnomAD4 genome AF: 0.819 AC: 124724 AN: 152258 Hom.: 53400 Cov.: 35 AF XY: 0.825 AC XY: 61395 AN XY: 74446

Gnomad4 AFR AF: 0.537

Gnomad4 AMR AF: 0.896

Gnomad4 ASJ AF: 0.924

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.956

Gnomad4 FIN AF: 0.958

Gnomad4 NFE AF: 0.920

Gnomad4 OTH AF: 0.848

Alfa AF: 0.877 Hom.: 26572

Bravo AF: 0.800

Asia WGS AF: 0.947 AC: 3292 AN: 3478

EpiCase AF: 0.915

EpiControl AF: 0.907

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Congenital myasthenic syndrome 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.6
DANN	Benign	0.32

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: rs10267; hg19: chr1-982994; COSMIC: COSV65071416; COSMIC: COSV65071416;