dbSNP rs373287346: AGRN:p.Ala1441Ala (chr1-1049260-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7

The NM_198576.4(AGRN):c.4323G>A(p.Ala1441Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,590,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

AGRN
NM_198576.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.41

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 1-1049260-G-A is Benign according to our data. Variant chr1-1049260-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 487335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.41 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGRN	NM_198576.4 link	c.4323G>A	p.Ala1441Ala	synonymous_variant	Exon 25 of 36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7 link	c.4323G>A	p.Ala1441Ala	synonymous_variant	Exon 25 of 36	1	NM_198576.4	ENSP00000368678.2		O00468-6

Frequencies

GnomAD3 genomes

AF:

0.000632

AC:

AN:

151986

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000228

AC:

AN:

219298

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

121284

show subpopulations

Gnomad AFR exome

AF:

0.00273

Gnomad AMR exome

AF:

0.000120

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000236

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000873

Gnomad NFE exome

AF:

0.0000299

Gnomad OTH exome

AF:

0.000364

GnomAD4 exome

AF:

0.000113

AC:

163

AN:

1438594

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

715126

show subpopulations

Gnomad4 AFR exome

AF:

0.00322

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.0000388

Gnomad4 EAS exome

AF:

0.000128

Gnomad4 SAS exome

AF:

0.0000354

Gnomad4 FIN exome

AF:

0.0000255

Gnomad4 NFE exome

AF:

0.0000199

Gnomad4 OTH exome

AF:

0.000201

GnomAD4 genome

AF:

0.000638

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00222

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000320

Hom.:

Bravo

AF:

0.000752

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 10, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AGRN: BP4, BP7 -

AGRN-related disorder

Benign:1

Jan 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Congenital myasthenic syndrome 8

Benign:1

Dec 24, 2024

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

-0.86

CADD

Benign

1.1

DANN

Benign

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over