chr1-1046833-G-C

Position:

chr1-1046833-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.3264G>C(p.Leu1088Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,585,702 control chromosomes in the GnomAD database, including 74 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. L1088?) has been classified as Benign.

Frequency

Genomes: 𝑓 0.013 ( 24 hom., cov: 33)

Exomes 𝑓: 0.0068 ( 50 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.22

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=0.0029761791).

BP6

Variant 1-1046833-G-C is Benign according to our data. Variant chr1-1046833-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 128298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1046833-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1954/152294) while in subpopulation AFR AF= 0.0309 (1285/41558). AF 95% confidence interval is 0.0295. There are 24 homozygotes in gnomad4. There are 894 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.3264G>C	p.Leu1088Phe	missense_variant	19/36	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.3264G>C	p.Leu1088Phe	missense_variant	19/36	1	NM_198576.4	ENSP00000368678	P1	O00468-6
AGRN	ENST00000651234.1 linkuse as main transcript	c.2949G>C	p.Leu983Phe	missense_variant	18/38			ENSP00000499046
AGRN	ENST00000652369.1 linkuse as main transcript	c.2949G>C	p.Leu983Phe	missense_variant	18/35			ENSP00000498543
AGRN	ENST00000620552.4 linkuse as main transcript	c.2850G>C	p.Leu950Phe	missense_variant	19/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1931

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0305

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00549

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00748

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00645

AC:

1299

AN:

201354

Hom.:

AF XY:

0.00597

AC XY:

652

AN XY:

109230

show subpopulations

Gnomad AFR exome

AF:

0.0285

Gnomad AMR exome

AF:

0.00406

Gnomad ASJ exome

AF:

0.00321

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00239

Gnomad FIN exome

AF:

0.00135

Gnomad NFE exome

AF:

0.00769

Gnomad OTH exome

AF:

0.00543

GnomAD4 exome

AF:

0.00677

AC:

9701

AN:

1433408

Hom.:

Cov.:

AF XY:

0.00664

AC XY:

4721

AN XY:

710890

show subpopulations

Gnomad4 AFR exome

AF:

0.0285

Gnomad4 AMR exome

AF:

0.00450

Gnomad4 ASJ exome

AF:

0.00337

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00349

Gnomad4 FIN exome

AF:

0.00134

Gnomad4 NFE exome

AF:

0.00688

Gnomad4 OTH exome

AF:

0.00745

GnomAD4 genome

AF:

0.0128

AC:

1954

AN:

152294

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

894

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0309

Gnomad4 AMR

AF:

0.00549

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00748

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00533

Hom.:

Bravo

AF:

0.0141

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.0289

AC:

126

ESP6500EA

AF:

0.00747

AC:

ExAC

AF:

0.00616

AC:

735

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 02, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital myasthenic syndrome 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.0030

DANN

Benign

0.43

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.073

T;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.90

L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.39

PROVEAN

Benign

0.59

N;.

REVEL

Benign

0.14

Sift

Benign

0.72

T;.

Sift4G

Benign

0.73

T;T

Vest4

0.074

MutPred

0.081

Gain of glycosylation at S1091 (P = 0.1278);.;

MVP

0.45

MPC

0.13

ClinPred

0.0021

GERP RS

-8.4

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

gMVP

0.21

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