1-1050785-G-A

Position:

chr1-1050785-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198576.4(AGRN):c.5201G>A(p.Arg1734His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,601,112 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1734C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0038 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 17 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.51

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01095891).

BP6

Variant 1-1050785-G-A is Benign according to our data. Variant chr1-1050785-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1050785-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00376 (572/152242) while in subpopulation NFE AF= 0.00435 (296/67980). AF 95% confidence interval is 0.00395. There are 3 homozygotes in gnomad4. There are 328 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 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.5201G>A	p.Arg1734His	missense_variant	30/36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AGRN	ENST00000379370.7 linkuse as main transcript	c.5201G>A	p.Arg1734His	missense_variant	30/36	1	NM_198576.4	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1 linkuse as main transcript	c.4886G>A	p.Arg1629His	missense_variant	29/38			ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.1 linkuse as main transcript	c.4886G>A	p.Arg1629His	missense_variant	29/35			ENSP00000498543.1	A0A494C0G5
AGRN	ENST00000620552.4 linkuse as main transcript	c.4787G>A	p.Arg1596His	missense_variant	30/39	5		ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0205

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00435

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00345

AC:

788

AN:

228248

Hom.:

AF XY:

0.00347

AC XY:

433

AN XY:

124778

show subpopulations

Gnomad AFR exome

AF:

0.000759

Gnomad AMR exome

AF:

0.000816

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000172

Gnomad FIN exome

AF:

0.0192

Gnomad NFE exome

AF:

0.00390

Gnomad OTH exome

AF:

0.00320

GnomAD4 exome

AF:

0.00386

AC:

5593

AN:

1448870

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

2718

AN XY:

720514

show subpopulations

Gnomad4 AFR exome

AF:

0.000360

Gnomad4 AMR exome

AF:

0.000822

Gnomad4 ASJ exome

AF:

0.00174

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.000270

Gnomad4 FIN exome

AF:

0.0174

Gnomad4 NFE exome

AF:

0.00402

Gnomad4 OTH exome

AF:

0.00299

GnomAD4 genome

AF:

0.00376

AC:

572

AN:

152242

Hom.:

Cov.:

AF XY:

0.00441

AC XY:

328

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0205

Gnomad4 NFE

AF:

0.00435

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00341

Hom.:

Bravo

AF:

0.00238

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00408

AC:

ExAC

AF:

0.00292

AC:

352

Asia WGS

AF:

0.000289

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 specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 27, 2017	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2019	This variant is associated with the following publications: (PMID: 19631309) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	AGRN: PP3, BS2 -

Congenital myasthenic syndrome 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

D;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.65

MVP

0.87

MPC

0.64

ClinPred

0.012

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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