rs79016973

Positions:

chr1-1043594-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.1660G>A(p.Val554Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,605,018 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0059 ( 51 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.44

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=0.017632931).

BP6

Variant 1-1043594-G-A is Benign according to our data. Variant chr1-1043594-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 263165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1043594-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00721 (1098/152322) while in subpopulation EAS AF= 0.0328 (170/5184). AF 95% confidence interval is 0.0288. There are 14 homozygotes in gnomad4. There are 617 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.1660G>A	p.Val554Met	missense_variant	9/36	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.1660G>A	p.Val554Met	missense_variant	9/36	1	NM_198576.4	ENSP00000368678	P1	O00468-6
AGRN	ENST00000651234.1 linkuse as main transcript	c.1345G>A	p.Val449Met	missense_variant	8/38			ENSP00000499046
AGRN	ENST00000652369.1 linkuse as main transcript	c.1345G>A	p.Val449Met	missense_variant	8/35			ENSP00000498543
AGRN	ENST00000620552.4 linkuse as main transcript	c.1246G>A	p.Val416Met	missense_variant	9/39	5		ENSP00000484607

Frequencies

GnomAD3 genomes

AF:

0.00721

AC:

1098

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.00595

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.0329

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0286

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00656

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00811

AC:

1933

AN:

238454

Hom.:

AF XY:

0.00804

AC XY:

1048

AN XY:

130422

show subpopulations

Gnomad AFR exome

AF:

0.000571

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00143

Gnomad EAS exome

AF:

0.0332

Gnomad SAS exome

AF:

0.00243

Gnomad FIN exome

AF:

0.0269

Gnomad NFE exome

AF:

0.00654

Gnomad OTH exome

AF:

0.00960

GnomAD4 exome

AF:

0.00594

AC:

8623

AN:

1452696

Hom.:

Cov.:

AF XY:

0.00597

AC XY:

4317

AN XY:

723116

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00168

Gnomad4 ASJ exome

AF:

0.00211

Gnomad4 EAS exome

AF:

0.0291

Gnomad4 SAS exome

AF:

0.00247

Gnomad4 FIN exome

AF:

0.0261

Gnomad4 NFE exome

AF:

0.00500

Gnomad4 OTH exome

AF:

0.00612

GnomAD4 genome

AF:

0.00721

AC:

1098

AN:

152322

Hom.:

Cov.:

AF XY:

0.00828

AC XY:

617

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.00595

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.0328

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.0286

Gnomad4 NFE

AF:

0.00656

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00656

Hom.:

Bravo

AF:

0.00526

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00865

AC:

1048

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.00463

EpiControl

AF:

0.00587

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 23, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

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 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.018

T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.0

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.9

N;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.011

D;.

Sift4G

Uncertain

0.024

D;D

Vest4

0.56

MVP

0.81

MPC

0.50

ClinPred

0.013

GERP RS

4.2

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

gMVP

0.47

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