chr1-1043288-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.67

Publications

1 publications found

Variant links:

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

AGRN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.1434G>A	p.Thr478Thr	synonymous_variant	Exon 8 of 36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
AGRN	ENST00000379370.7 link	c.1434G>A	p.Thr478Thr	synonymous_variant	Exon 8 of 36	1	NM_198576.4	ENSP00000368678.2
AGRN	ENST00000651234.1 link	c.1119G>A	p.Thr373Thr	synonymous_variant	Exon 7 of 38			ENSP00000499046.1
AGRN	ENST00000652369.2 link	c.1119G>A	p.Thr373Thr	synonymous_variant	Exon 7 of 35			ENSP00000498543.1
AGRN	ENST00000620552.4 link	c.1020G>A	p.Thr340Thr	synonymous_variant	Exon 8 of 39	5		ENSP00000484607.1

Frequencies

GnomAD3 genomes

AF:

0.00276

AC:

420

AN:

152202

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00408

AC XY:

2961

AN XY:

725914

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33472

American (AMR)

AF:

0.00119

AC:

AN:

44464

Ashkenazi Jewish (ASJ)

AF:

0.0122

AC:

318

AN:

26026

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39616

South Asian (SAS)

AF:

0.00178

AC:

153

AN:

85824

European-Finnish (FIN)

AF:

0.000438

AC:

AN:

52520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00468

AC:

5199

AN:

1111488

Other (OTH)

AF:

0.00592

AC:

357

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

438

877

1315

1754

2192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

212

424

636

848

1060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00276

AC:

420

AN:

152320

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

177

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41574

American (AMR)

AF:

0.00196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00187

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00443

AC:

301

AN:

68018

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00414

Hom.:

Bravo

AF:

0.00287

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.22

(source)

DANN

Benign

0.51

PhyloP100

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over