1-1048333-C-T

Position:

chr1-1048333-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_198576.4(AGRN):c.4073C>T(p.Pro1358Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000848 in 1,473,532 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1358P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 1 hom. )

Consequence

AGRN
NM_198576.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.56

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0900431).

BP6

Variant 1-1048333-C-T is Benign according to our data. Variant chr1-1048333-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 579825.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4 linkuse as main transcript	c.4073C>T	p.Pro1358Leu	missense_variant	23/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7 linkuse as main transcript	c.4073C>T	p.Pro1358Leu	missense_variant	23/36	1	NM_198576.4	P1	O00468-6
AGRN	ENST00000651234.1 linkuse as main transcript	c.3758C>T	p.Pro1253Leu	missense_variant	22/38
AGRN	ENST00000652369.1 linkuse as main transcript	c.3758C>T	p.Pro1253Leu	missense_variant	22/35
AGRN	ENST00000620552.4 linkuse as main transcript	c.3659C>T	p.Pro1220Leu	missense_variant	23/39	5

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000166

AC:

AN:

84394

Hom.:

AF XY:

0.000161

AC XY:

AN XY:

43472

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000207

Gnomad ASJ exome

AF:

0.00325

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000684

Gnomad OTH exome

AF:

0.000414

GnomAD4 exome

AF:

0.0000840

AC:

111

AN:

1321402

Hom.:

Cov.:

AF XY:

0.0000887

AC XY:

AN XY:

642536

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00253

Gnomad4 EAS exome

AF:

0.0000841

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000442

Gnomad4 OTH exome

AF:

0.000128

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000396

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000584

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

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

Jan 24, 2024

The c.4073C>T (p.P1358L) alteration is located in exon 23 (coding exon 23) of the AGRN gene. This alteration results from a C to T substitution at nucleotide position 4073, causing the proline (P) at amino acid position 1358 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myasthenic syndrome 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

-0.024

Eigen_PC

Benign

-0.059

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.090

T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.7

D;.

REVEL

Uncertain

0.54

Sift

Uncertain

0.0080

D;.

Sift4G

Uncertain

0.0020

D;D

Vest4

0.27

MVP

0.92

MPC

0.30

ClinPred

0.19

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.62

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