chr1-1045488-G-A

Position:

chr1-1045488-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000379370.7(AGRN):c.2501G>A(p.Arg834Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00132 in 1,612,966 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R834E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

AGRN
ENST00000379370.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 6.31

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056515425).

BP6

Variant 1-1045488-G-A is Benign according to our data. Variant chr1-1045488-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 387869.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.2501G>A	p.Arg834Gln	missense_variant	14/36	ENST00000379370.7	NP_940978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGRN	ENST00000379370.7 linkuse as main transcript	c.2501G>A	p.Arg834Gln	missense_variant	14/36	1	NM_198576.4	ENSP00000368678	P1	O00468-6

Frequencies

GnomAD3 genomes

AF:

0.000966

AC:

147

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00163

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00116

AC:

289

AN:

250056

Hom.:

AF XY:

0.00131

AC XY:

178

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.000495

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00196

Gnomad FIN exome

AF:

0.000464

Gnomad NFE exome

AF:

0.00179

Gnomad OTH exome

AF:

0.000819

GnomAD4 exome

AF:

0.00136

AC:

1982

AN:

1460626

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

983

AN XY:

726600

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00152

Gnomad4 FIN exome

AF:

0.000555

Gnomad4 NFE exome

AF:

0.00156

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.000965

AC:

147

AN:

152340

Hom.:

Cov.:

AF XY:

0.000953

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00163

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00164

Hom.:

Bravo

AF:

0.000952

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00129

AC:

156

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27397848) -

AGRN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2023

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.057

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.6

D;.

REVEL

Uncertain

0.33

Sift

Benign

0.14

T;.

Sift4G

Uncertain

0.0090

D;D

Vest4

0.61

MVP

0.79

MPC

0.36

ClinPred

0.052

GERP RS

5.4

gMVP

0.44

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

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