chr1-1045488-G-A

Position:

• chr1-1045488-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_198576.4(AGRN):​c.2501G>A​(p.Arg834Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00132 in 1,612,966 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. R834E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: AGRN NM_198576.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 6.31

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056515425).
• BP6: Variant 1-1045488-G-A is Benign according to our data. Variant chr1-1045488-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 387869.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGRN	NM_198576.4	c.2501G>A	p.Arg834Gln	missense_variant	14/36	ENST00000379370.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGRN	ENST00000379370.7	c.2501G>A	p.Arg834Gln	missense_variant	14/36	1	NM_198576.4	P1

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152222 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00116 AC: 289 AN: 250056 Hom.: 0 AF XY: 0.00131 AC XY: 178 AN XY: 135604

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.00136 AC: 1982 AN: 1460626 Hom.: 3 Cov.: 34 AF XY: 0.00135 AC XY: 983 AN XY: 726600

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.000555

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000965 AC: 147 AN: 152340 Hom.: 0 Cov.: 34 AF XY: 0.000953 AC XY: 71 AN XY: 74496

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.000952

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00129 AC: 156

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27397848) -

AGRN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 06, 2023

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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Uncertain	0.33
Sift	Benign	0.14	T;.
Sift4G	Uncertain	0.0090	D;D
Vest4		0.61
MVP		0.79
MPC		0.36
ClinPred		0.052	T
GERP RS		5.4
gMVP		0.44

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

Other links and lift over

dbSNP: rs146243145; hg19: chr1-980868;