1-1044368-A-T

Position:

chr1-1044368-A-T

Variant summary

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

The NM_198576.4(AGRN):c.2183A>T(p.Glu728Val) variant causes a missense change. The variant allele was found at a frequency of 0.0373 in 1,612,466 control chromosomes in the GnomAD database, including 1,296 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 105 hom., cov: 33)

Exomes 𝑓: 0.038 ( 1191 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.45

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=0.0125976205).

BP6

Variant 1-1044368-A-T is Benign according to our data. Variant chr1-1044368-A-T is described in ClinVar as [Benign]. Clinvar id is 128294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1044368-A-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0294 (4473/151964) while in subpopulation NFE AF= 0.0448 (3044/67948). AF 95% confidence interval is 0.0435. There are 105 homozygotes in gnomad4. There are 2142 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 105 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.2183A>T	p.Glu728Val	missense_variant	12/36	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.2183A>T	p.Glu728Val	missense_variant	12/36	1	NM_198576.4	ENSP00000368678	P1	O00468-6
AGRN	ENST00000651234.1 linkuse as main transcript	c.1868A>T	p.Glu623Val	missense_variant	11/38			ENSP00000499046
AGRN	ENST00000652369.1 linkuse as main transcript	c.1868A>T	p.Glu623Val	missense_variant	11/35			ENSP00000498543
AGRN	ENST00000620552.4 linkuse as main transcript	c.1769A>T	p.Glu590Val	missense_variant	12/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes

AF:

0.0295

AC:

4477

AN:

151846

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00673

Gnomad AMI

AF:

0.0736

Gnomad AMR

AF:

0.0214

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.00503

Gnomad SAS

AF:

0.0281

Gnomad FIN

AF:

0.0388

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0448

Gnomad OTH

AF:

0.0255

GnomAD3 exomes

AF:

0.0298

AC:

7415

AN:

249164

Hom.:

152

AF XY:

0.0308

AC XY:

4169

AN XY:

135286

show subpopulations

Gnomad AFR exome

AF:

0.00636

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.0438

Gnomad EAS exome

AF:

0.00419

Gnomad SAS exome

AF:

0.0221

Gnomad FIN exome

AF:

0.0373

Gnomad NFE exome

AF:

0.0409

Gnomad OTH exome

AF:

0.0339

GnomAD4 exome

AF:

0.0381

AC:

55625

AN:

1460502

Hom.:

1191

Cov.:

AF XY:

0.0381

AC XY:

27654

AN XY:

726578

show subpopulations

Gnomad4 AFR exome

AF:

0.00511

Gnomad4 AMR exome

AF:

0.0160

Gnomad4 ASJ exome

AF:

0.0437

Gnomad4 EAS exome

AF:

0.00292

Gnomad4 SAS exome

AF:

0.0235

Gnomad4 FIN exome

AF:

0.0348

Gnomad4 NFE exome

AF:

0.0425

Gnomad4 OTH exome

AF:

0.0359

GnomAD4 genome

AF:

0.0294

AC:

4473

AN:

151964

Hom.:

105

Cov.:

AF XY:

0.0288

AC XY:

2142

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00671

Gnomad4 AMR

AF:

0.0213

Gnomad4 ASJ

AF:

0.0349

Gnomad4 EAS

AF:

0.00504

Gnomad4 SAS

AF:

0.0281

Gnomad4 FIN

AF:

0.0388

Gnomad4 NFE

AF:

0.0448

Gnomad4 OTH

AF:

0.0253

Alfa

AF:

0.0395

Hom.:

Bravo

AF:

0.0269

TwinsUK

AF:

0.0340

AC:

126

ALSPAC

AF:

0.0322

AC:

124

ESP6500AA

AF:

0.00863

AC:

ESP6500EA

AF:

0.0426

AC:

366

ExAC

AF:

0.0292

AC:

3543

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0436

EpiControl

AF:

0.0411

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided

Benign:1

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

-0.47

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.8

D;.

REVEL

Benign

0.23

Sift

Benign

0.036

D;.

Sift4G

Uncertain

0.0020

D;D

Vest4

0.69

MPC

0.58

ClinPred

0.016

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.68

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