chr1-1048126-C-T

Position:

chr1-1048126-C-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.3866C>T(p.Pro1289Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,570,118 control chromosomes in the GnomAD database, including 34 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. P1289S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0063 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0060 ( 29 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.61

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=0.003664583).

BP6

Variant 1-1048126-C-T is Benign according to our data. Variant chr1-1048126-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1048126-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00629 (958/152314) while in subpopulation AFR AF= 0.009 (374/41558). AF 95% confidence interval is 0.00825. There are 5 homozygotes in gnomad4. There are 452 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.3866C>T	p.Pro1289Leu	missense_variant	23/36	ENST00000379370.7	NP_940978.2	O00468-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AGRN	ENST00000379370.7 linkuse as main transcript	c.3866C>T	p.Pro1289Leu	missense_variant	23/36	1	NM_198576.4	ENSP00000368678.2	O00468-6
AGRN	ENST00000651234.1 linkuse as main transcript	c.3551C>T	p.Pro1184Leu	missense_variant	22/38			ENSP00000499046.1	A0A494C1I6
AGRN	ENST00000652369.1 linkuse as main transcript	c.3551C>T	p.Pro1184Leu	missense_variant	22/35			ENSP00000498543.1	A0A494C0G5
AGRN	ENST00000620552.4 linkuse as main transcript	c.3452C>T	p.Pro1151Leu	missense_variant	23/39	5		ENSP00000484607.1	A0A087X208

Frequencies

GnomAD3 genomes

AF:

0.00628

AC:

956

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00898

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00386

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00695

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00496

AC:

899

AN:

181330

Hom.:

AF XY:

0.00488

AC XY:

484

AN XY:

99256

show subpopulations

Gnomad AFR exome

AF:

0.00953

Gnomad AMR exome

AF:

0.00284

Gnomad ASJ exome

AF:

0.000564

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00223

Gnomad FIN exome

AF:

0.00141

Gnomad NFE exome

AF:

0.00779

Gnomad OTH exome

AF:

0.00472

GnomAD4 exome

AF:

0.00596

AC:

8454

AN:

1417804

Hom.:

Cov.:

AF XY:

0.00587

AC XY:

4129

AN XY:

703066

show subpopulations

Gnomad4 AFR exome

AF:

0.00937

Gnomad4 AMR exome

AF:

0.00308

Gnomad4 ASJ exome

AF:

0.000821

Gnomad4 EAS exome

AF:

0.0000269

Gnomad4 SAS exome

AF:

0.00305

Gnomad4 FIN exome

AF:

0.00134

Gnomad4 NFE exome

AF:

0.00672

Gnomad4 OTH exome

AF:

0.00498

GnomAD4 genome

AF:

0.00629

AC:

958

AN:

152314

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

452

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00900

Gnomad4 AMR

AF:

0.00385

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00695

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00676

Hom.:

Bravo

AF:

0.00696

ESP6500AA

AF:

0.00652

AC:

ESP6500EA

AF:

0.00682

AC:

ExAC

AF:

0.00439

AC:

518

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 25, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	AGRN: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

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	PreventionGenetics, part of Exact Sciences	-	- -

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

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.35

DANN

Benign

0.66

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0085

LIST_S2

Benign

0.26

T;T

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.81

N;.

PrimateAI

Benign

0.40

PROVEAN

Benign

0.29

N;.

REVEL

Benign

0.059

Sift

Benign

0.40

T;.

Sift4G

Benign

1.0

T;T

Vest4

0.092

MVP

0.54

MPC

0.12

ClinPred

0.0028

GERP RS

-4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.14

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