1-1049746-G-C

Position:

chr1-1049746-G-C

Variant summary

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

The NM_198576.4(AGRN):c.4695G>C(p.Gln1565His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,579,520 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict 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. Q1565R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0074 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00071 ( 15 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.430

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006070763).

BP6

Variant 1-1049746-G-C is Benign according to our data. Variant chr1-1049746-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 387480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00736 (1111/151014) while in subpopulation AFR AF= 0.0259 (1062/41082). AF 95% confidence interval is 0.0246. There are 7 homozygotes in gnomad4. There are 529 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.4695G>C	p.Gln1565His	missense_variant	26/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7 linkuse as main transcript	c.4695G>C	p.Gln1565His	missense_variant	26/36	1	NM_198576.4	P1	O00468-6
AGRN	ENST00000651234.1 linkuse as main transcript	c.4380G>C	p.Gln1460His	missense_variant	25/38
AGRN	ENST00000652369.1 linkuse as main transcript	c.4380G>C	p.Gln1460His	missense_variant	25/35
AGRN	ENST00000620552.4 linkuse as main transcript	c.4281G>C	p.Gln1427His	missense_variant	26/39	5

Frequencies

GnomAD3 genomes

AF:

0.00736

AC:

1111

AN:

150896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0259

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00217

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:

0.0000592

Gnomad OTH

AF:

0.00576

GnomAD3 exomes

AF:

0.00177

AC:

328

AN:

185194

Hom.:

AF XY:

0.00115

AC XY:

117

AN XY:

102010

show subpopulations

Gnomad AFR exome

AF:

0.0292

Gnomad AMR exome

AF:

0.000773

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000385

Gnomad OTH exome

AF:

0.00103

GnomAD4 exome

AF:

0.000715

AC:

1021

AN:

1428506

Hom.:

Cov.:

AF XY:

0.000575

AC XY:

407

AN XY:

707854

show subpopulations

Gnomad4 AFR exome

AF:

0.0272

Gnomad4 AMR exome

AF:

0.00115

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000100

Gnomad4 OTH exome

AF:

0.00112

GnomAD4 genome

AF:

0.00736

AC:

1111

AN:

151014

Hom.:

Cov.:

AF XY:

0.00717

AC XY:

529

AN XY:

73818

show subpopulations

Gnomad4 AFR

AF:

0.0259

Gnomad4 AMR

AF:

0.00217

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000592

Gnomad4 OTH

AF:

0.00570

Alfa

AF:

0.000720

Hom.:

Bravo

AF:

0.00850

ESP6500AA

AF:

0.0244

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00171

AC:

200

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2021

- -

AGRN-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2019

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.41

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.29

Sift

Benign

0.21

T;.

Sift4G

Benign

0.22

T;T

Vest4

0.27

MutPred

0.36

Gain of catalytic residue at L1567 (P = 0.0732);.;

MVP

0.91

MPC

0.15

ClinPred

0.0025

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.59

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