rs144245019

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198576.4(AGRN):c.5353G>A(p.Asp1785Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00951 in 1,566,410 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0068 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0098 ( 86 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.0220

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0104987025).

BP6

Variant 1-1051352-G-A is Benign according to our data. Variant chr1-1051352-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128314.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr1-1051352-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00677 (1030/152056) while in subpopulation NFE AF= 0.0115 (778/67918). AF 95% confidence interval is 0.0108. There are 1 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 86 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.5353G>A	p.Asp1785Asn	missense_variant	31/36	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.5353G>A	p.Asp1785Asn	missense_variant	31/36	1	NM_198576.4	ENSP00000368678	P1	O00468-6
AGRN	ENST00000651234.1 linkuse as main transcript	c.5050G>A	p.Asp1684Asn	missense_variant	31/38			ENSP00000499046
AGRN	ENST00000652369.1 linkuse as main transcript	c.5038G>A	p.Asp1680Asn	missense_variant	30/35			ENSP00000498543
AGRN	ENST00000620552.4 linkuse as main transcript	c.4951G>A	p.Asp1651Asn	missense_variant	32/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes

AF:

0.00679

AC:

1031

AN:

151938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00232

Gnomad AMI

AF:

0.00769

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00237

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0115

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00633

AC:

1089

AN:

172002

Hom.:

AF XY:

0.00614

AC XY:

567

AN XY:

92368

show subpopulations

Gnomad AFR exome

AF:

0.00164

Gnomad AMR exome

AF:

0.00443

Gnomad ASJ exome

AF:

0.00764

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000953

Gnomad FIN exome

AF:

0.00315

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.00624

GnomAD4 exome

AF:

0.00980

AC:

13859

AN:

1414354

Hom.:

Cov.:

AF XY:

0.00972

AC XY:

6798

AN XY:

699158

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00476

Gnomad4 ASJ exome

AF:

0.00708

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00117

Gnomad4 FIN exome

AF:

0.00271

Gnomad4 NFE exome

AF:

0.0117

Gnomad4 OTH exome

AF:

0.00766

GnomAD4 genome

AF:

0.00677

AC:

1030

AN:

152056

Hom.:

Cov.:

AF XY:

0.00601

AC XY:

447

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00231

Gnomad4 AMR

AF:

0.00503

Gnomad4 ASJ

AF:

0.00807

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00237

Gnomad4 NFE

AF:

0.0115

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00959

Hom.:

Bravo

AF:

0.00710

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.0106

AC:

ESP6500AA

AF:

0.00230

AC:

ESP6500EA

AF:

0.0116

AC:

ExAC

AF:

0.00511

AC:

595

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	AGRN: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2013	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.5

DANN

Benign

0.95

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.18

T;T

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.12

N;.

REVEL

Benign

0.069

Sift

Benign

0.56

T;.

Sift4G

Benign

0.48

T;T

Vest4

0.18

MVP

0.48

MPC

0.12

ClinPred

0.0023

GERP RS

-2.1

gMVP

0.38

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