1-1047561-T-C

Variant names:

• chr1-1047561-T-C
• rs3128102
• NM_198576.4:c.3517-12T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198576.4(AGRN):​c.3517-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.898 in 1,612,772 control chromosomes in the GnomAD database, including 659,170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (51070 hom., cov: 36)
  • Exomes 𝑓: 0.91 (608100 hom.)
• Consequence: AGRN NM_198576.4 intron
• Scores: Splicing: ADA: 0.00005620
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.147
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-1047561-T-C is Benign according to our data. Variant chr1-1047561-T-C is described in ClinVar as Benign. ClinVar VariationId is 263181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4	c.3517-12T>C		intron_variant	Intron 20 of 35	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7	c.3517-12T>C		intron_variant	Intron 20 of 35	1	NM_198576.4	ENSP00000368678.2

Frequencies

GnomAD3 genomes AF: 0.794 AC: 120768 AN: 152128 Hom.: 51078 Cov.: 36

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.986

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.968

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.917

Gnomad OTH AF: 0.830

GnomAD2 exomes AF: 0.896 AC: 223530 AN: 249388 AF XY: 0.904

Gnomad AFR exome AF: 0.447

Gnomad AMR exome AF: 0.932

Gnomad ASJ exome AF: 0.917

Gnomad EAS exome AF: 0.973

Gnomad FIN exome AF: 0.933

Gnomad NFE exome AF: 0.913

Gnomad OTH exome AF: 0.899

GnomAD4 exome AF: 0.909 AC: 1328134 AN: 1460526 Hom.: 608100 Cov.: 63 AF XY: 0.912 AC XY: 662285 AN XY: 726556

African (AFR) AF: 0.439 AC: 14712 AN: 33476

American (AMR) AF: 0.925 AC: 41382 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 23898 AN: 26136

East Asian (EAS) AF: 0.970 AC: 38501 AN: 39700

South Asian (SAS) AF: 0.943 AC: 81360 AN: 86258

European-Finnish (FIN) AF: 0.932 AC: 48600 AN: 52126

Middle Eastern (MID) AF: 0.851 AC: 4911 AN: 5768

European-Non Finnish (NFE) AF: 0.918 AC: 1021024 AN: 1111962

Other (OTH) AF: 0.890 AC: 53746 AN: 60380

GnomAD4 genome AF: 0.793 AC: 120782 AN: 152246 Hom.: 51070 Cov.: 36 AF XY: 0.798 AC XY: 59434 AN XY: 74448

African (AFR) AF: 0.463 AC: 19216 AN: 41498

American (AMR) AF: 0.884 AC: 13530 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.920 AC: 3194 AN: 3472

East Asian (EAS) AF: 0.968 AC: 5006 AN: 5172

South Asian (SAS) AF: 0.946 AC: 4570 AN: 4830

European-Finnish (FIN) AF: 0.939 AC: 9969 AN: 10620

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.917 AC: 62385 AN: 68024

Other (OTH) AF: 0.831 AC: 1756 AN: 2112

Alfa AF: 0.867 Hom.: 12044

Bravo AF: 0.773

Asia WGS AF: 0.922 AC: 3207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.1
DANN	Benign	0.34
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000056
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3128102; hg19: chr1-982941;