rs779170859

Positions:

chr1-1041197-T-C

Variant summary

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

The NM_198576.4(AGRN):c.752T>C(p.Val251Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000161 in 1,462,122 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V251M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 31)

Exomes 𝑓: 0.000044 ( 1 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 5.65

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=0.009522587).

BP6

Variant 1-1041197-T-C is Benign according to our data. Variant chr1-1041197-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430121.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00118 (178/151120) while in subpopulation AFR AF= 0.00411 (169/41094). AF 95% confidence interval is 0.00361. There are 2 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.752T>C	p.Val251Ala	missense_variant	5/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7 linkuse as main transcript	c.752T>C	p.Val251Ala	missense_variant	5/36	1	NM_198576.4	P1	O00468-6

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

178

AN:

151014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00412

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000295

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000102

AC:

AN:

78762

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

45518

show subpopulations

Gnomad AFR exome

AF:

0.00559

Gnomad AMR exome

AF:

0.0000690

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:

0.0000329

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000442

AC:

AN:

1311002

Hom.:

Cov.:

AF XY:

0.0000340

AC XY:

AN XY:

647120

show subpopulations

Gnomad4 AFR exome

AF:

0.00158

Gnomad4 AMR exome

AF:

0.0000390

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000138

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000478

Gnomad4 OTH exome

AF:

0.000186

GnomAD4 genome

AF:

0.00118

AC:

178

AN:

151120

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

73878

show subpopulations

Gnomad4 AFR

AF:

0.00411

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00199

Hom.:

ExAC

AF:

0.0000596

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.752T>C (p.V251A) alteration is located in exon 5 (coding exon 5) of the AGRN gene. This alteration results from a T to C substitution at nucleotide position 752, causing the valine (V) at amino acid position 251 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2020

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

AGRN-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2022

This variant is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.0095

T;T

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.8

N;.

REVEL

Uncertain

0.35

Sift

Benign

0.10

T;.

Sift4G

Benign

0.12

T;D

Vest4

0.44

MutPred

0.24

Loss of stability (P = 0.0254);.;

MVP

0.84

MPC

0.64

ClinPred

0.058

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.65

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