1-1043288-G-A

Variant names:

• chr1-1043288-G-A
• rs147346337
• NM_198576.4:c.1434G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198576.4(AGRN):​c.1434G>A​(p.Thr478Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,611,818 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (24 hom.)
• Consequence: AGRN NM_198576.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.67
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-1043288-G-A is Benign according to our data. Variant chr1-1043288-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00276 (420/152320) while in subpopulation NFE AF = 0.00443 (301/68018). AF 95% confidence interval is 0.00401. There are 1 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	NM_198576.4	MANE Select	c.1434G>A	p.Thr478Thr	synonymous	Exon 8 of 36	NP_940978.2
	AGRN	NM_001305275.2		c.1434G>A	p.Thr478Thr	synonymous	Exon 8 of 39	NP_001292204.1
	AGRN	NM_001364727.2		c.1119G>A	p.Thr373Thr	synonymous	Exon 7 of 36	NP_001351656.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGRN	ENST00000379370.7	TSL:1 MANE Select	c.1434G>A	p.Thr478Thr	synonymous	Exon 8 of 36	ENSP00000368678.2
	AGRN	ENST00000651234.1		c.1119G>A	p.Thr373Thr	synonymous	Exon 7 of 38	ENSP00000499046.1
	AGRN	ENST00000652369.2		c.1119G>A	p.Thr373Thr	synonymous	Exon 7 of 35	ENSP00000498543.1

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00442

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00272 AC: 667 AN: 244910 AF XY: 0.00283

Gnomad AFR exome AF: 0.000698

Gnomad AMR exome AF: 0.00129

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000388

Gnomad NFE exome AF: 0.00375

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00420 AC: 6126 AN: 1459498 Hom.: 24 Cov.: 35 AF XY: 0.00408 AC XY: 2961 AN XY: 725914

African (AFR) AF: 0.000627 AC: 21 AN: 33472

American (AMR) AF: 0.00119 AC: 53 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 318 AN: 26026

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39616

South Asian (SAS) AF: 0.00178 AC: 153 AN: 85824

European-Finnish (FIN) AF: 0.000438 AC: 23 AN: 52520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00468 AC: 5199 AN: 1111488

Other (OTH) AF: 0.00592 AC: 357 AN: 60324

GnomAD4 genome AF: 0.00276 AC: 420 AN: 152320 Hom.: 1 Cov.: 33 AF XY: 0.00238 AC XY: 177 AN XY: 74480

African (AFR) AF: 0.000794 AC: 33 AN: 41574

American (AMR) AF: 0.00196 AC: 30 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00443 AC: 301 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00414 Hom.: 1

Bravo AF: 0.00287

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 13, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AGRN: BP4, BP7, BS2

Mar 05, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myasthenic syndrome 8 Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.22
DANN	Benign	0.51
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs147346337; hg19: chr1-978668; COSMIC: COSV65069060; COSMIC: COSV65069060;